Effects of long-term hypoxemia on pituitary-adrenal function in fetal sheep

1996 ◽  
Vol 271 (4) ◽  
pp. E678-E685 ◽  
Author(s):  
J. Murotsuki ◽  
R. Gagnon ◽  
S. G. Matthews ◽  
J. R. Challis
Keyword(s):  
Adrenal Function ◽  
Arterial Oxygen ◽  
Pars Intermedia ◽  
Mrna Levels ◽  
Pars Distalis ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Pomc Mrna ◽  
Pregnant Sheep

To test the hypothesis that long-term hypoxemia causes premature activation of the fetal pituitary-adrenal function, we embolized the fetal side of the placenta in pregnant sheep and examined the changes in concentrations of immunoreactive adrenocorticotropic hormone (irACTH), cortisol, and prostaglandin E2 (PGE2) in fetal plasma, and levels and localization of proopiomelanocortin (POMC) mRNA in the pars distalis and the pars intermedia of the fetal pituitary. Twelve fetal sheep were studied (6 embolized and 6 control) for 21 days between 0.74 and 0.88 of gestation. Daily injections of nonradiolabeled microspheres were given into the fetal abdominal aorta to decrease fetal arterial oxygen content by 40-50% of the preembolization values. In the embolized group, concentrations of irACTH, PGE2, and cortisol in fetal plasma increased gradually and were significantly (P < 0.05) elevated above those of controls after day 10, day 16, and day 20, respectively. POMC mRNA levels in the pars distalis of the fetal pituitary were not different from those of controls but were significantly reduced in the pars intermedia (P < 0.05). We conclude that levels of POMC mRNA in the pars distalis are unchanged during long-term hypoxemia possibly because of negative feedback effects of elevated cortisol on the pituitary gland. During long-term fetal hypoxemia, there is a differential regulation of POMC mRNA expression in the pars distalis and pars intermedia.

Levels of pro-opiomelanocortin and prolactin mRNA in the fetal sheep pituitary following hypoxaemia and glucocorticoid treatment in late gestation

1995 ◽  
Vol 147 (1) ◽  
pp. 139-146 ◽  
Author(s):  
S G Matthews ◽  
J R G Challis
Keyword(s):  
Late Gestation ◽  
Pars Intermedia ◽  
Mrna Levels ◽  
Glucocorticoid Treatment ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Pomc Mrna ◽  
Highly Sensitive ◽  
Ovine Fetal

Abstract It is well established that corticotrophin-releasing hormone and vasopressin can induce both synthesis and release of ACTH from the ovine pituitary gland, and that glucocorticoids can inhibit these responses. Changes in the abundance, localization and distribution of proopiomelanocortin (POMC) mRNA and prolactin (PRL) mRNA in the ovine fetal pituitary were examined by in situ hybridization following hypoxaemia applied in the presence or absence of concomitant cortisol in late gestation (day 135). Fetuses were distributed amongst four groups; saline-infused/normoxaemic, cortisol-infused/normoxaemic (0·3 mg/h), saline-infused/hypoxaemic and cortisol-infused/hypoxaemic. Hypoxaemia (6 h) was induced by reducing the maternal PaO2, resulting in a 6–8 mmHg decrease in fetal arterial PO2. Fetal infusions were commenced 5 h prior to and maintained throughout the treatment period. Hypoxaemia, which elevated fetal plasma ACTH and cortisol, caused a significant (P<0·05) increase in POMC mRNA in the pars distalis (PD), but was without effect on POMC mRNA in the pars intermedia (PI). Cortisol infusion attenuated the hypoxaemiainduced increase in POMC mRNA in the PD, but was without effect on non-stimulated steady-state POMC mRNA levels in either the PD or PI. PRL mRNA was only present in the PD and significantly (P<0·05) increased after cortisol infusion and hypoxaemia. In conclusion (i) POMC and PRL mRNA in the PD are increased following moderate hypoxaemia, (ii) cortisol attenuates changes in POMC mRNA but not PRL mRNA in the PD following hypoxaemia and (iii) cortisol increases PRL mRNA levels in the PD. Synthesis of POMC and PRL in the fetal PD is highly sensitive to homeostatic perturbations and glucocorticoids in late gestation. Journal of Endocrinology (1995) 147, 139–146

Divergent changes in plasma ACTH and pituitary POMC mRNA after cortisol administration to late-gestation ovine fetus

1998 ◽  
Vol 274 (3) ◽  
pp. E417-E425 ◽  
Author(s):  
T. M. Jeffray ◽  
S. G. Matthews ◽  
G. L. Hammond ◽  
J. R. G. Challis
Keyword(s):  
Plasma Cortisol ◽  
Late Gestation ◽  
Pars Intermedia ◽  
Mrna Levels ◽  
Plasma Acth ◽  
Negative Feedback Regulation ◽  
Fetal Sheep ◽  
Pomc Mrna ◽  
Free Cortisol ◽  
Ovine Fetus

Plasma concentrations of cortisol and adrenocorticotropic hormone (ACTH) rise in the late-gestation sheep fetus at approximately the same time as there is an increase in the plasma levels of corticosteroid- binding globulin (CBG). We hypothesized that intrafetal cortisol infusion during late pregnancy would stimulate an increase in fetal plasma CBG, which in turn would bind cortisol and diminish glucocorticoid negative-feedback regulation of the fetal pituitary, leading to an increase in plasma ACTH concentrations. Cortisol was infused into chronically catheterized fetal sheep beginning at 126.1 ± 0.5 days of gestation and continued for 96 h. Control fetuses were infused with saline. In cortisol-infused fetuses, the plasma cortisol concentrations rose significantly from control levels (4.4 ± 0.6 ng/ml) to 19.3 ± 3.1 ng/ml within 24 h and remained significantly elevated throughout the infusion period. Plasma immunoreactive (ir) ACTH concentrations were significantly elevated in cortisol-infused fetuses within 24–48 h and remained significantly higher than in controls throughout the 96-h experimental period. Plasma free cortisol concentrations increased 10-fold and remained significantly elevated in cortisol-infused animals, despite a rise in plasma corticosteroid-binding capacity. Levels of pituitary proopiomelanocortin (POMC) mRNA in the fetal pars distalis and pars intermedia were 96 and 38% lower, respectively, after 96 h of cortisol infusion. Therefore physiological elevations of plasma cortisol, in the late-gestation ovine fetus, lead to increases in mean plasma irACTH concentrations, but this is not associated with increases in fetal pituitary POMC mRNA levels.

Pro-opiomelanocortin messenger RNA levels increase in the fetal sheep pituitary during late gestation

1991 ◽  
Vol 131 (3) ◽  
pp. 483-489 ◽  
Author(s):  
K. Yang ◽  
J. R. G. Challis ◽  
V. K. M. Han ◽  
G. L. Hammond
Keyword(s):  
Messenger Rna ◽  
Blot Hybridization ◽  
Late Gestation ◽  
Northern Blot Hybridization ◽  
Mrna Levels ◽  
Plasma Acth ◽  
Mrna Accumulation ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Pomc Mrna

ABSTRACT Plasma levels of ACTH and cortisol in fetal sheep increase progressively during late pregnancy, providing the stimulus for birth. However, little information is available concerning either sources of pro-opiomelanocortin (POMC, the precursor to ACTH) or changes in POMC gene expression, which may be responsible for the elevated fetal plasma ACTH concentrations. We therefore studied the relative amount of POMC mRNA in fetal sheep hypothalami, anterior pituitaries and adrenals at discrete times of pregnancy between day 60 and term (approximately 145 days) and from newborn lambs. Total RNA from these tissues was analysed by Northern blot hybridization using a human POMC DNA probe, and the amount of POMC mRNA was expressed relative to the signal obtained for 18S ribosomal RNA. A single 1·2 kb transcript was detected by day 60 in the anterior pituitary, and its relative amount did not change significantly until after days 125–130. Pituitary POMC mRNA levels increased significantly at days 138–143, remained elevated at term and increased further in newborn lambs. In contrast, POMC mRNA was undetectable in hypothalami and adrenal glands of fetuses at all ages. The results suggested that the prepartum rise in plasma ACTH concentrations in fetal sheep is due to increased POMC biosynthesis in the fetal pituitary. The increase in POMC mRNA occurs at a time when fetal plasma cortisol concentrations are elevated, indicating that the negative feedback effects of circulating glucocorticoids on the fetal hypothalamicpituitary axis may be obscured by other mechanisms that increase pituitary POMC mRNA accumulation during the last week of gestation. Journal of Endocrinology (1991) 131, 483–489

scholarly journals Subpopulations of Corticotrophs in the Sheep Pituitary during Late Gestation: Effects of Development and Placental Restriction

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4762-4771 ◽  
Author(s):  
Kirsten Farrand ◽  
I. Caroline McMillen ◽  
Shigeyasu Tanaka ◽  
Jeffrey Schwartz
Keyword(s):  
Late Gestation ◽  
Mrna Levels ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Pomc Mrna ◽  
Experimental Induction ◽  
Attachment Sites ◽  
Specific Antisera

The prepartum surge in fetal plasma cortisol is essential for the normal timing of parturition in sheep and may result from an increase in the ratio of ACTH to proopiomelanocortin (POMC) in the fetal circulation. In fetuses subjected to experimental induction of placental restriction, the prepartum surge in fetal cortisol is exaggerated, whereas pituitary POMC mRNA levels are decreased, and in vitro, unstimulated ACTH secretion is elevated in corticotrophs nonresponsive to CRH. We therefore investigated the changes in the relative proportions of cells expressing POMC, ACTH, and the CRH type 1 receptor (CRHR1) shortly before birth and during chronic placental insufficiency. Placental restriction (PR) was induced by removal of the majority of placental attachment sites in five ewes before mating. Pituitaries were collected from control and PR fetal sheep at 140 d (control, n = 4; PR, n = 4) and 144 d (control, n = 6; PR, n = 4). Pituitary sections were labeled with specific antisera raised against POMC, ACTH, and CRHR1. Three major subpopulations of corticotrophs were identified that expressed POMC + ACTH + CRHR1, ACTH + CRHR1, or POMC only. The proportion of pituitary corticotrophs expressing POMC + ACTH + CRHR1 decreased (P &lt; 0.05) between 140 (control, 60 ± 1%; PR, 66 ± 4%) and 144 (control, 45 ± 2%; PR, 56 ± 6%) d. A significantly higher (P &lt; 0.05) proportion of corticotrophs expressed POMC + ACTH + CRHR1 in the pituitary of the PR group compared with controls. This study is the first to demonstrate subpopulations of corticotrophs in the fetal sheep pituitary that differentially express POMC, ACTH, and CRHR1 and the separate effects of gestational age and placental restriction on these subpopulations of corticotrophs.

Developmental changes in the distribution of pro-opiomelanocortin and prolactin mRNA in the pituitary of the ovine fetus and lamb

1994 ◽  
Vol 13 (2) ◽  
pp. 175-185 ◽  
Author(s):  
S G Matthews ◽  
X Han ◽  
F Lu ◽  
J R G Challis
Keyword(s):  
Late Gestation ◽  
Pars Intermedia ◽  
Fetal Life ◽  
Mrna Levels ◽  
Pars Distalis ◽  
Pomc Mrna ◽  
Inferior Aspect ◽  
Ovine Fetus ◽  
Pomc Gene

ABSTRACT Ontogenic changes in pituitary pro-opiomelanocortin (POMC) mRNA and prolactin (PRL) mRNA were examined during gestation and early neonatal life using in situ hybridization histochemistry. Pituitaries were harvested from fetuses at days 60–80, 100–120, 135–140 and 142–143 of gestation and at term, and from lambs at days 1–7 and 30–60 of age and adults. POMC mRNA, present by day 60, rose during mid- and late gestation. Concurrently there was a change in corticotroph distribution, resulting in a relatively greater quantity of POMC mRNA at the base of the pars distalis. At term, there was a significant (P<0·05) further elevation of POMC mRNA. POMC mRNA levels remained high in the newborn lamb but decreased in the adult. Cells in the pars intermedia expressed large amounts of POMC mRNA early in fetal life and this pattern persisted throughout gestation and into the neonatal period. Changes in the expression of the POMC gene correlated closely with the presence of immunoreactive (ir)ACTH in the pituitary; in fetuses the proportion of irACTH-positive cells rose to 10% of pars distalis cells by day 100 and did not change significantly thereafter. The lactotrophs contained PRL mRNA by day 60, and the quantity increased towards parturition (P<0·05). PRL mRNA subsequently decreased in the neonate, but rose as the lamb matured. These results indicate that in the fetal pituitary: (1) the POMC gene is highly expressed during gestation in both the pars distalis and the pars intermedia, (2) changes in the amounts of POMC mRNA and PRL mRNA in the pars distalis correlate with the distribution of irACTH and irPRL respectively, and (3) POMC mRNA is distributed primarily in the inferior aspect of the pars distalis, and in this region its quantity is highest immediately prior to parturition.

Atrial natriuretic factor in maternal and fetal sheep

1987 ◽  
Vol 252 (2) ◽  
pp. E279-E282 ◽  
Author(s):  
C. Y. Cheung ◽  
D. M. Gibbs ◽  
R. A. Brace
Keyword(s):  
Atrial Natriuretic Factor ◽  
Allantoic Fluid ◽  
Maternal Plasma ◽  
Fetal Kidney ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Natriuretic Factor ◽  
Pregnant Sheep ◽  
Fetal Urine ◽  
Atrial Natriuretic

To determine atrial natriuretic factor (ANF) concentrations in the circulation and body fluids of adult pregnant sheep and their fetuses, pregnant ewes were anesthetized with pentobarbital sodium, and the fetuses were exteriorized for sampling. ANF concentration, as measured by radioimmunoassay, was 47 +/- 6 (SE) pg/ml in maternal plasma, which was significantly higher than the 15 +/- 3 pg/ml in maternal urine. In the fetus, plasma ANF concentration was 265 +/- 49 pg/ml, 5.6 times that in maternal plasma. No umbilical arterial and venous difference in ANF concentration was observed. Fetal urine ANF concentration (13 +/- 2 pg/ml) was significantly lower than that in fetal plasma, and was similar to that measured in amniotic and allantoic fluid. In chronically catheterized maternal and fetal sheep, fetal plasma ANF was again 5.1 times that in maternal plasma, and these levels were not different from those measured in acutely anesthetized animals. These results demonstrate that immunoreactive ANF is present in the fetal circulation at levels higher than those found in the mother. The low concentration of ANF in fetal urine suggests that ANF is probably metabolized and/or reabsorbed by the fetal kidney.

scholarly journals Adrenocortical and Adipose Responses to High-Altitude-Induced, Long-Term Hypoxia in the Ovine Fetus

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Dean A. Myers ◽  
Charles A. Ducsay
Keyword(s):  
High Altitude ◽  
Hpa Axis ◽  
Anterior Pituitary ◽  
Late Gestation ◽  
Integrative Model ◽  
Adaptive Responses ◽  
Fetal Plasma ◽  
Pregnant Sheep ◽  
The Impact

By late gestation, the maturing hypothalamo-pituitary-adrenal (HPA) axis aids the fetus in responding to stress. Hypoxia represents a significant threat to the fetus accompanying situations such as preeclampsia, smoking, high altitude, and preterm labor. We developed a model of high-altitude (3,820 m), long-term hypoxia (LTH) in pregnant sheep. We describe the impact of LTH on the fetal HPA axis at the level of the hypothalamic paraventricular nucleus (PVN), anterior pituitary corticotrope, and adrenal cortex. At the PVN and anterior pituitary, the responses to LTH are consistent with hypoxia being a potent activator of the HPA axis and potentially maladaptive, while the adrenocortical response to LTH appears to be primarily adaptive. We discuss mechanisms involved in the delicate balance between these seemingly opposing responses that preserve the normal ontogenic rise in fetal plasma cortisol essential for organ maturation and in this species, birth. Further, we examine the response to, and ramifications of, an acute secondary stressor in the LTH fetus. We provide an integrative model on the potential role of adipose in modulating these responses to LTH. Integration of these adaptive responses to LTH plays a key role in promoting normal fetal growth and development under conditions of a chronic stress.

Expression, distribution, regulation and function of IGFs in the ovine fetal pituitary

1995 ◽  
Vol 14 (3) ◽  
pp. 323-336 ◽  
Author(s):  
F Lü ◽  
K Yang ◽  
V K M Han ◽  
J R G Challis
Keyword(s):  
Pituitary Gland ◽  
Endocrine Cells ◽  
Cell Types ◽  
Pars Intermedia ◽  
Pars Distalis ◽  
Paracrine Factors ◽  
Pomc Mrna ◽  
Pars Nervosa ◽  
Igf I ◽  
And Function

ABSTRACT Activation of the fetal pituitary-adrenal axis is crucial for fetal organ maturation and the onset of parturition in sheep. Many factors including corticotrophin-releasing hormone (CRH) and arginine vasopressin secreted from the hypothalamus, and growth factors produced within the pituitary may be involved in the regulation of maturation of the fetal pituitary gland. IGFs have mitogenic and differentiation-promoting capacities in a variety of organs and are synthesized as paracrine factors within developing tissues. However, there is little information concerning the synthesis, distribution, regulation and function of IGFs in the fetal pituitary gland at different times during pregnancy. Therefore, we have localized IGF-I and IGF-II mRNAs and peptides, and determined the effect of cortisol on the level of IGF-II mRNAs in the pituitary glands of developing sheep fetuses. We examined the possible effects of IGFs on corticotroph function in cultures of adenohypophysial cells from term fetuses. Seven species of IGF-II transcripts of 1·2–6·0 kb were identified by Northern blot analysis in the pituitary gland of fetuses between day 60 of gestation and term (day 145). The levels of IGF-II mRNAs did not change significantly during pregnancy, although there was a trend for the presence of higher levels of IGF-II mRNAs at day 60 of gestation. IGF-I mRNA was not detectable. By in situ hybridization, IGF-II mRNA was localized to non-endocrine cells and to cells lining the blood vessels of the pars distalis, to some presumed endocrine cells in the pars distalis and pars intermedia, and to clusters of cells in the pars nervosa. In contrast, IGF-I and IGF-II peptides were detected in the presumed endocrine cells in the pars distalis and pars intermedia but not in the pars nervosa. Incubation of adenohypophysial cells from term fetuses with IGF-I, but not IGF-II, for 48 h increased specific 125I-Tyr-ovine CRH binding. However, neither IGF-I nor IGF-II had any significant effects on the basal or CRH-stimulated immunoreactive (ir)-ACTH output, the level of POMC mRNA or the number of ir-ACTH positive cells. Infusion of cortisol to fetuses starting at day 96 of gestation for 100 h or at days 120–125 of gestation for 84 h did not affect the level of IGF-II mRNAs in the pars distalis but decreased the levels of POMC mRNA. These results are consistent with IGFs having the potential to influence fetal pituitary function, although probably on cell types other than the corticotrophs. The likely sources of IGFs may be predominantly local (IGF-II) or from extrapituitary sources (IGF-I).

scholarly journals Experimental hyperthyroidism and central mediators of stress axis and thyroid axis activity in common carp (Cyprinus carpio L.)

2006 ◽  
Vol 37 (3) ◽  
pp. 443-452 ◽  
Author(s):  
Edwin J W Geven ◽  
Folkert Verkaar ◽  
Gert Flik ◽  
Peter H M Klaren
Keyword(s):  
Common Carp ◽  
Cyprinus Carpio ◽  
Plasma Cortisol ◽  
Stress Axis ◽  
Pars Intermedia ◽  
Mrna Levels ◽  
Experimental Hyperthyroidism ◽  
Pomc Mrna ◽  
Hpi Axis ◽  
Thyroid Axis

The effect of experimental hyperthyroidism, realized by T4 injection, on central mediators of the hypothalamo–pituitary–interrenal axis (HPI-axis) in common carp (Cyprinus carpio L.) was studied. Our results show that hyperthyroidism evokes a marked 3.2-fold reduction in basal plasma cortisol levels. Corticotropin-releasing hormone-binding protein (CRH-BP) mRNA levels in the hypothalamus, measured by real-time quantitative PCR, were significantly elevated by 40%, but CRH, urotensin-I, prepro-TRH, prohormone convertase-1 (PC1), and POMC mRNA levels were unchanged. In the pituitary pars distalis, PC1, CRH receptor-1, and POMC mRNA levels were unaffected, as was ACTH content. Plasma α-MSH concentrations were significantly elevated by 30% in hyperthyroid fish, and this was reflected in PC1 and POMC mRNA levels in pituitary pars intermedia that were increased 1.5- and 2.4-fold respectively. The α-MSH content of the pars intermedia was unchanged. Hyperthyroidism has profound effects on the basal levels of a central mediator, i.e., CRH-BP, of HPI-axis function in unstressed carp in vivo, and we conclude that HPI- and hypothalamo–pituitary–thyroid-axis functions are strongly interrelated. We suggest that the changes in plasma cortisol, thyroid hormone, and α-MSH levels reflect their concerted actions on energy metabolism.

scholarly journals Proopiomelanocortin Processing in the Anterior Pituitary of the Ovine Fetus after Lesion of the Hypothalamic Paraventricular Nucleus

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2665-2673 ◽  
Author(s):  
M. Elizabeth Bell ◽  
Thomas J. McDonald ◽  
Dean A. Myers
Keyword(s):  
Paraventricular Nucleus ◽  
Anterior Pituitary ◽  
Limit Of Detection ◽  
Plasma Concentrations ◽  
Hybridization Signal ◽  
Mrna Levels ◽  
Fetal Sheep ◽  
Fetal Plasma ◽  
Ovine Fetus ◽  
Fetal Organs

Abstract The hypothalamic-pituitary-adrenocortical axis plays an essential role in the maturation of fetal organs and, in sheep, birth. Lesioning the paraventricular nucleus (PVN) in fetal sheep prevents adrenocortical maturation and parturition without altering plasma immunoreactive ACTH concentrations. The purpose of this study was to determine the effect of PVN lesion on anterior pituitary processing of proopiomelanocortin (POMC) to ACTH, plasma concentrations of ACTH and ACTH precursors (POMC; 22-kDa proACTH), and expression of subtilisin-like prohormone convertase 3 (SPC3) in corticotropes in fetal sheep. PVN lesion did not affect anterior pituitary POMC and 22-kDa proACTH levels, whereas ACTH was significantly affected. The ACTH precursor (POMC plus 22-kDa proACTH) to ACTH ratio in the anterior pituitary was significantly increased after PVN lesion. Post-PVN lesion, fetal plasma ACTH1–39, was below the limit of detection, whereas ACTH precursors (POMC plus 22-kDa proACTH) were not affected. In the inferior region of the anterior pituitary, 40–50% of corticotropes had detectable SPC3 hybridization signal, and PVN lesion did not change the extent of colocalization of POMC and SPC3, or SPC3 mRNA levels within corticotropes. Neither the percent of corticotropes in the superior region containing SPC3 hybridization (7–12%) or hybridization signal strength was altered in response to PVN lesion. In conclusion, the fetal PVN is necessary for sustaining adequate anterior pituitary processing of POMC to ACTH and ACTH release needed for maturing the adrenal cortex in the sheep fetus.

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