OBJECTIVEdFactors associated with increasing maternal triglyceride concentrations in late pregnan... more OBJECTIVEdFactors associated with increasing maternal triglyceride concentrations in late pregnancy include gestational age, obesity, preeclampsia, and altered glucose metabolism. In a subgroup of women in the Metformin in Gestational Diabetes (MiG) trial, maternal plasma triglycerides increased more between enrollment (30 weeks) and 36 weeks in those treated with metformin compared with insulin. The aim of this study was to explain this finding by examining factors potentially related to triglycerides in these women.
We have investigated the effects of restriction of placental growth on foetal adrenal growth and ... more We have investigated the effects of restriction of placental growth on foetal adrenal growth and adrenal expression of mRNAs for Insulin-like Growth Factor II (IGF-II), the IGF binding protein IGFBP-2, Steroidogenic Factor 1 (SF-1) and adrenocorticotrophic hormone (ACTH) receptor (ACTH-R) and the steroidogenic cytochrome P-450 enzymes: cholesterol side chain cleavage (CYP11A1), 17alpha-hydroxylase (CYP17) and 21-hydroxylase (CYP21A1); and 3beta-hydroxysteroid dehydrogenase/Delta5Delta4 isomerase (3betaHSD). Endometrial caruncles were removed from non-pregnant ewes before mating (placental restriction group; PR). The total adrenal: foetal weight ratio was higher in PR (n=6 foetuses) than in control foetuses (n=6 foetuses). There was no difference in plasma ACTH concentrations between the PR and control foetuses between 130 and 140 days gestation. Adrenal IGF-II mRNA levels were lower (P<0.05) in the PR group, however, adrenal IGFBP-2 mRNA levels were not different between the PR and control groups. Adrenal ACTH-R mRNA levels were also lower whilst CYP11A1 mRNA levels were increased (P<0.005) in the PR group. We conclude that foetal adrenal growth and steroidogenesis are stimulated as a consequence of foetal growth restriction and that factors other than ACTH are important in foetal adrenal activation during chronic, sustained hypoxaemia.
We have investigated the effects of a 5 day infusion of cortisol into fetal sheep, in which the h... more We have investigated the effects of a 5 day infusion of cortisol into fetal sheep, in which the hypothalamus and pituitary were surgically disconnected (HPD), on fetal pituitary-adrenal function. Fetal HPD and vascular catheterization were carried out at between 104 and 124 days gestation. Cortisol was administered (3.5 mg 24 h−1) for 120 h between 134 and 140 days (HPD+F group; n=5) and saline was administered during the same gestational age range to HPD (HPD group; n=12) and intact fetal sheep (Intact group; n=6). Cortisol infusion into the HPD fetal sheep did not suppress the mRNA levels for Proopiomelanocortin (POMC) in the fetal anterior pituitary at 139/140 days gestation (POMC mRNA: 18S rRNA: Intact 0.40±0.05; HPD 0.56±0.07; HPD+F 0.49±0.07). Similarly, there was no significant effect of either HPD or cortisol infusion on the plasma concentrations of immunoreactive (ir) ACTH or ACTH(1–39). The adrenal: fetal body weight ratio was significantly higher, however, in the HPD+F (88.4±8.7 mg kg−1) and Intact groups (84.1±5.6 mg kg−1) when compared with the HPD fetal sheep (63.7±5.4 mg kg−1). The ratio of total IGF-II mRNA: 18S rRNA was similar in the adrenals of the Intact (0.48±0.09), HPD (0.78±0.09) and HPD+F (0.71±0.11) groups. The ratios of CYPIIA1, 3b-HSD and CYP21A1 mRNA: 18S rRNA were significantly lower in adrenals from the HPD group when compared to those in the Intact group and were not restored to normal by cortisol infusion. We have therefore demonstrated that cor tisol does not act directly at the fetal pituitary to suppress POMC synthesis or ACTH secretion in late gestation. Cortisol does, however, stimulate fetal adrenal growth after HPD in the absence of any effects on adrenal IGF-II or steroidogenic enzyme mRNA levels. The data provide evidence that an intact hypothalamic-pituitar y axis and cor tisol each play an important role in the stimulation of adrenal growth and steroidogenesis which occurs during the last 10–15 days of gestation in the sheep. Parturition in the sheep is dependent on the prepartum increase cortisol acts in the slow time domain at the fetal pituitary, we have infused cortisol for 5 days from around 135 days gestation in the fetal plasma concentrations of immunoreactive (ir) ACTH and cortisol (term=147±3 days (d) gestation) (1). The concomit-in HPD fetal sheep and have measured POMC mRNA levels in the fetal anterior pituitary and circulating irACTH during the ant rise in fetal plasma ACTH and cortisol before delivery is intriguing as several studies have clearly demonstrated that short infusion period. We have also previously demonstrated that the late gestational and long-term infusions of glucocorticoids can inhibit basal and stimulus induced increases in fetal plasma ACTH concentrations increase in plasma ACTH(1–39) concentrations, adrenal growth and adrenal steroidogenic enzyme expression in the sheep fetus (2–8). There have been no studies, however, on the neuroendo-crine site of action of cortisol acting in the slow time domain are dependent on an intact and functional hypothalamo-pituitary axis (11). It remains unclear, however, how adrenal growth and (i.e.>8 h) on the synthesis of the ACTH precursor, Proopiomelanocortin (POMC) in the fetal pituitary and on steroidogenesis are regulated during the last 15 days of gestation. Chromatographic studies have shown that irACTH is present in ACTH secretion. We have previously described a method of surgical disconnection of the fetal hypothalamus and pituitary the fetal circulation in a range of molecular weight forms including the bioactive ACTH(1–39) and the high molecular weight ACTH (hypothalamo-pituitary disconnection; HPD) at around 110 days gestation which results in minimal infarction of the fetal anterior precursors (POMC and Pro-ACTH) (12). One possibility therefore is that in late gestation, the coordinate regulation of fetal pituitary and does not diminish the fetal ACTH response to an exogenous bolus of Corticotrophin Releasing Hormone (CRH) adrenal growth, steroidogenesis and cortisol output is dependent on changes in the post translational processing of POMC in the (7, 9). Whilst circulating irACTH concentrations are maintained or are higher in fetal sheep after HPD, there is no prepartum fetal pituitary which in turn requires the action of a hypothalamic secretagogue. A second possibility, however, is that the functional cortisol increase after 135 d gestation and gestation is therefore prolonged in the HPD fetus (10). In order to determine whether changes in the pituitary-adrenal axis in late gestation are, in part,
We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression o... more We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 microg/kg.h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline-infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine-synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation.
American Journal of Obstetrics and Gynecology, 2004
Objective: The aim of this study was to determine the long-term effects of chronic placental insu... more Objective: The aim of this study was to determine the long-term effects of chronic placental insufficiency on the metabolic state and organ structure in the fetal and adolescent guinea pig. Study design: The maternal uterine artery was ligated at day 28-30 to reduce placental function and restrict fetal growth. Whole body and tissue weights and plasma metabolites were determined at 60 days of gestation and 8 weeks of age; tissue structure was determined at the latter age in restricted and control offspring. Results: Fetal growth restriction increased fibrosis in the heart and kidneys (P ! .05), increased aortic wall thickening (P ! .01), reduced the number of glomeruli in the kidneys (P ! .05), and increased the plasma urea and chloride in adolescent offspring. Conclusion: This study demonstrates that diseases in the heart, aorta, and kidneys that result from an adverse prenatal environment are evident at adolescence and may contribute to subsequent adult disease.
OBJECTIVEdFactors associated with increasing maternal triglyceride concentrations in late pregnan... more OBJECTIVEdFactors associated with increasing maternal triglyceride concentrations in late pregnancy include gestational age, obesity, preeclampsia, and altered glucose metabolism. In a subgroup of women in the Metformin in Gestational Diabetes (MiG) trial, maternal plasma triglycerides increased more between enrollment (30 weeks) and 36 weeks in those treated with metformin compared with insulin. The aim of this study was to explain this finding by examining factors potentially related to triglycerides in these women.
We have investigated the effects of restriction of placental growth on foetal adrenal growth and ... more We have investigated the effects of restriction of placental growth on foetal adrenal growth and adrenal expression of mRNAs for Insulin-like Growth Factor II (IGF-II), the IGF binding protein IGFBP-2, Steroidogenic Factor 1 (SF-1) and adrenocorticotrophic hormone (ACTH) receptor (ACTH-R) and the steroidogenic cytochrome P-450 enzymes: cholesterol side chain cleavage (CYP11A1), 17alpha-hydroxylase (CYP17) and 21-hydroxylase (CYP21A1); and 3beta-hydroxysteroid dehydrogenase/Delta5Delta4 isomerase (3betaHSD). Endometrial caruncles were removed from non-pregnant ewes before mating (placental restriction group; PR). The total adrenal: foetal weight ratio was higher in PR (n=6 foetuses) than in control foetuses (n=6 foetuses). There was no difference in plasma ACTH concentrations between the PR and control foetuses between 130 and 140 days gestation. Adrenal IGF-II mRNA levels were lower (P<0.05) in the PR group, however, adrenal IGFBP-2 mRNA levels were not different between the PR and control groups. Adrenal ACTH-R mRNA levels were also lower whilst CYP11A1 mRNA levels were increased (P<0.005) in the PR group. We conclude that foetal adrenal growth and steroidogenesis are stimulated as a consequence of foetal growth restriction and that factors other than ACTH are important in foetal adrenal activation during chronic, sustained hypoxaemia.
We have investigated the effects of a 5 day infusion of cortisol into fetal sheep, in which the h... more We have investigated the effects of a 5 day infusion of cortisol into fetal sheep, in which the hypothalamus and pituitary were surgically disconnected (HPD), on fetal pituitary-adrenal function. Fetal HPD and vascular catheterization were carried out at between 104 and 124 days gestation. Cortisol was administered (3.5 mg 24 h−1) for 120 h between 134 and 140 days (HPD+F group; n=5) and saline was administered during the same gestational age range to HPD (HPD group; n=12) and intact fetal sheep (Intact group; n=6). Cortisol infusion into the HPD fetal sheep did not suppress the mRNA levels for Proopiomelanocortin (POMC) in the fetal anterior pituitary at 139/140 days gestation (POMC mRNA: 18S rRNA: Intact 0.40±0.05; HPD 0.56±0.07; HPD+F 0.49±0.07). Similarly, there was no significant effect of either HPD or cortisol infusion on the plasma concentrations of immunoreactive (ir) ACTH or ACTH(1–39). The adrenal: fetal body weight ratio was significantly higher, however, in the HPD+F (88.4±8.7 mg kg−1) and Intact groups (84.1±5.6 mg kg−1) when compared with the HPD fetal sheep (63.7±5.4 mg kg−1). The ratio of total IGF-II mRNA: 18S rRNA was similar in the adrenals of the Intact (0.48±0.09), HPD (0.78±0.09) and HPD+F (0.71±0.11) groups. The ratios of CYPIIA1, 3b-HSD and CYP21A1 mRNA: 18S rRNA were significantly lower in adrenals from the HPD group when compared to those in the Intact group and were not restored to normal by cortisol infusion. We have therefore demonstrated that cor tisol does not act directly at the fetal pituitary to suppress POMC synthesis or ACTH secretion in late gestation. Cortisol does, however, stimulate fetal adrenal growth after HPD in the absence of any effects on adrenal IGF-II or steroidogenic enzyme mRNA levels. The data provide evidence that an intact hypothalamic-pituitar y axis and cor tisol each play an important role in the stimulation of adrenal growth and steroidogenesis which occurs during the last 10–15 days of gestation in the sheep. Parturition in the sheep is dependent on the prepartum increase cortisol acts in the slow time domain at the fetal pituitary, we have infused cortisol for 5 days from around 135 days gestation in the fetal plasma concentrations of immunoreactive (ir) ACTH and cortisol (term=147±3 days (d) gestation) (1). The concomit-in HPD fetal sheep and have measured POMC mRNA levels in the fetal anterior pituitary and circulating irACTH during the ant rise in fetal plasma ACTH and cortisol before delivery is intriguing as several studies have clearly demonstrated that short infusion period. We have also previously demonstrated that the late gestational and long-term infusions of glucocorticoids can inhibit basal and stimulus induced increases in fetal plasma ACTH concentrations increase in plasma ACTH(1–39) concentrations, adrenal growth and adrenal steroidogenic enzyme expression in the sheep fetus (2–8). There have been no studies, however, on the neuroendo-crine site of action of cortisol acting in the slow time domain are dependent on an intact and functional hypothalamo-pituitary axis (11). It remains unclear, however, how adrenal growth and (i.e.>8 h) on the synthesis of the ACTH precursor, Proopiomelanocortin (POMC) in the fetal pituitary and on steroidogenesis are regulated during the last 15 days of gestation. Chromatographic studies have shown that irACTH is present in ACTH secretion. We have previously described a method of surgical disconnection of the fetal hypothalamus and pituitary the fetal circulation in a range of molecular weight forms including the bioactive ACTH(1–39) and the high molecular weight ACTH (hypothalamo-pituitary disconnection; HPD) at around 110 days gestation which results in minimal infarction of the fetal anterior precursors (POMC and Pro-ACTH) (12). One possibility therefore is that in late gestation, the coordinate regulation of fetal pituitary and does not diminish the fetal ACTH response to an exogenous bolus of Corticotrophin Releasing Hormone (CRH) adrenal growth, steroidogenesis and cortisol output is dependent on changes in the post translational processing of POMC in the (7, 9). Whilst circulating irACTH concentrations are maintained or are higher in fetal sheep after HPD, there is no prepartum fetal pituitary which in turn requires the action of a hypothalamic secretagogue. A second possibility, however, is that the functional cortisol increase after 135 d gestation and gestation is therefore prolonged in the HPD fetus (10). In order to determine whether changes in the pituitary-adrenal axis in late gestation are, in part,
We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression o... more We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 microg/kg.h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline-infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine-synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation.
American Journal of Obstetrics and Gynecology, 2004
Objective: The aim of this study was to determine the long-term effects of chronic placental insu... more Objective: The aim of this study was to determine the long-term effects of chronic placental insufficiency on the metabolic state and organ structure in the fetal and adolescent guinea pig. Study design: The maternal uterine artery was ligated at day 28-30 to reduce placental function and restrict fetal growth. Whole body and tissue weights and plasma metabolites were determined at 60 days of gestation and 8 weeks of age; tissue structure was determined at the latter age in restricted and control offspring. Results: Fetal growth restriction increased fibrosis in the heart and kidneys (P ! .05), increased aortic wall thickening (P ! .01), reduced the number of glomeruli in the kidneys (P ! .05), and increased the plasma urea and chloride in adolescent offspring. Conclusion: This study demonstrates that diseases in the heart, aorta, and kidneys that result from an adverse prenatal environment are evident at adolescence and may contribute to subsequent adult disease.
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