In Vivo Evidence for Increased Adrenal Sensitivity to Adrenocorticotropin-(l–24) in the Lamb Fetus Late in Gestation*

Rose, James C.; Meis, Paul J.; Urban, R. B.; Greiss, Frank C.

doi:10.1210/endo-111-1-80

Cited by 70 publications

(17 citation statements)

References 16 publications

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“…The pattern of change in ACTH-R mRNA levels observed in this study is closely associated with the final phase of adrenocortical growth (Boshier & Holloway 1989), and occurs simultaneously with the known increase in sensitivity of the fetal sheep adrenal gland to ACTH stimulation late in gestation (Rose et al 1982, Glickman & Challis 1980. Recently, Wang et al (1999), using ribonuclease protection assay analysis, also reported an increase in ACTH-R mRNA between day 100 and day 140 of gestation, but did not include time periods in between, or the time of parturition and the neonatal period.…”

Section: Discussionsupporting

confidence: 66%

Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxia during late pregnancy

Fraser

Braems²,

Challis³

2001

Journal of Endocrinology

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Responsiveness of the fetal sheep adrenal gland to adrenocorticotrophin (ACTH) increases in late pregnancy, resulting in increased glucocorticoid production. Development of this responsiveness is an important determinant of fetal hypothalamic-pituitary-adrenal function and depends, in part, on the potential for ACTH binding to adrenal tissue. In the present study, we have examined the developmental pattern of ACTH receptor (ACTH-R) expression during the latter half of pregnancy and in neonatal and adult life. As hypoxaemia induces increases in cortisol and ACTH secretion, in addition to increasing fetal adrenal responsiveness, a further aim of this study was to investigate whether hypoxaemia was associated with altered expression of the ACTH-R gene.Whole adrenal glands were removed from fetal sheep, lambs and adult sheep at different stages of development for measurement of ACTH-R mRNA. Moderate hypoxaemia was induced for 48 h beginning on days 124-128, or on days 132-134 of gestation, by decreasing the maternal fractional inspired oxygen. ACTH-R mRNA was detected by northern blotting using a cDNA cloned in our laboratory and by in situ bydridisation.ACTH-R mRNA (3·6 kb major transcript) was detected in adrenal tissue at day 63 of gestation. Its relative abundance increased significantly (P<0·05) between days 126-128 and 140-141 of pregnancy, increased further with the onset of spontaneous labour, and remained increased in newborn lambs at 7 h-7 days after birth. ACTH-R mRNA levels then decreased in adrenal tissue from lambs and adult sheep (P<0·05). Hypoxaemia for 48 h significantly increased ACTH-R mRNA expression in adrenals of the older fetuses (days 134-136) compared with that in controls (P<0·05), but was without effect in younger fetuses.We conclude that levels of ACTH-R mRNA in the fetal adrenal gland increase as term approaches, coincident with the endogenous prepartum surge in plasma ACTH and cortisol. Sustained hypoxaemia resulted in an upregulation of mRNA encoding for ACTH-R, but only in older fetuses and in association with a sustained increase in plasma cortisol. These results are consistent with cortisol, ACTH, or both, contributing to increased fetal adrenal responsiveness, by increasing expression of fetal adrenal receptors for ACTH.

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Section: Discussionsupporting

confidence: 66%

Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxia during late pregnancy

Fraser

Braems²,

Challis³

2001

Journal of Endocrinology

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“…An intact hypothalamic pituitary connection is essential, as clearly demonstrated by hypothalamic pituitary disconnection (HPD) studies in fetal sheep, in which the major consequences of this disruption are the absence of the cortisol surge (11,34,38,48,53) and delayed parturition (1, 2, 4, 33). Increased adrenal responsiveness also is a critical mediating factor (18,21,41,51). Two important effectors to this end, the adrenocorticotropic hormone receptor (ACTH-R, specifically known as the melanocortin-2 receptor) and steroid acute regulatory protein (StAR), exhibit ontogenic increases in expression that occur in parallel to the cortisol surge (8,17,49).…”

mentioning

confidence: 99%

Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep

Carey¹,

Su²,

Valego³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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-The late-gestation plasma cortisol surge in the sheep fetus is critical for stimulating organ development and parturition. Increased adrenal responsiveness is one of the key reasons for the surge; however, the underlying mechanisms are not fully understood. Our recent studies suggest that ACTH-mediated increased expression of ACTH receptor (ACTH-R) and steroid acute regulatory protein (StAR) may play a role in enhancing responsiveness. Hence, we examined effects of ACTH infusion in fetal sheep on mRNA expression of these two mediators of adrenal responsiveness and assessed the functional consequences of this treatment in vitro. Fetuses of ϳ118 and 138 days of gestational age (dGA) were infused with ACTH-(1-24) for 24 h. Controls received saline infusion. Arterial blood was sampled throughout the infusion. Adrenals were isolated and analyzed for ACTH-R and StAR mRNA, or cells were cultured for 48 h. Cells were stimulated with ACTH, and medium was collected for cortisol measurement. Fetal plasma ACTH and cortisol concentrations increased over the infusion period in both groups. ACTH-R mRNA levels were significantly higher in ACTH-infused fetuses in both the 118 and 138 dGA groups. StAR mRNA increased significantly in both the 118 and 138 dGA groups. Adrenal cells from ACTH-infused fetuses were significantly more responsive to ACTH stimulation in terms of cortisol secretion than those from saline-infused controls. These findings demonstrate that increases in circulating ACTH levels promote increased expression of ACTH-R and StAR mRNA and are coupled to heightened adrenal responsiveness. adrenocorticotropic hormone; ovine fetus IN HUMANS AND MANY MAMMALIAN SPECIES, the late-gestation surge in fetal plasma cortisol levels stimulates final stage development of the lung and other organ systems (7, 22) and indeed, in sheep, initiates birth (19, 32). Parturition occurring before this surge is associated with increased fetal mortality and morbidity, most notably as a consequence of lung immaturity. Whereas the sequence of events leading to cortisol production per se are well understood, the precise mechanisms involved in driving the rise in fetal plasma cortisol in late gestation are yet to be fully explained.It is apparent that important changes take place at each level of the hypothalamic-pituitary adrenal axis, leading to the prepartum increase in fetal plasma cortisol. An intact hypothalamic pituitary connection is essential, as clearly demonstrated by hypothalamic pituitary disconnection (HPD) studies in fetal sheep, in which the major consequences of this disruption are the absence of the cortisol surge (11,34,38,48,53) and delayed parturition (1, 2, 4, 33). Increased adrenal responsiveness also is a critical mediating factor (18,21,41,51). Two important effectors to this end, the adrenocorticotropic hormone receptor (ACTH-R, specifically known as the melanocortin-2 receptor) and steroid acute regulatory protein (StAR), exhibit ontogenic increases in expression that occur in parallel to the cortisol surge (8,17,49)...

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“…In singleton gestations and in sheep this increase in resting levels appears to be connected with an increase in response to exogenous ACTH, which occurs during gestation (25). Schwartz & Rose (10) have demonstrated that in fetal sheep twins the cortisol concentration in one sibling rises and remains at a higher level than that in the other.…”

Section: Discussionmentioning

confidence: 99%

Impaired adrenocortical function in very low birth weight infants after multiple pregnancies

Eskola

Lenko²,

Tammela³

2003

European Journal of Endocrinology

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Objective: To evaluate the differences in adrenal function between very low birth weight (VLBW) infants from singleton and multiple pregnancies. Design and methods: Forty infants of birth weights less than 1500 g underwent an ACTH test. Thirty infants born from singleton pregnancies (singleton group) and ten born from multiple pregnancies (multiple group) were enrolled. A baseline blood sample was drawn for cortisol measurement and thereafter serum cortisol was measured 1 and 2 h after an i.v. injection of ACTH. Results: In multiple pregnancies, the median basal cortisol level of the infants was significantly lower than that in the singletons. The median cortisol level at 1 and 2 h after administration of ACTH was significantly lower in infants from multiple gestations than in singletons. Of infants from the multiple gestation group six, and of the singleton infants 12, had baseline cortisol levels lower than the reference values (P ¼ 0.48). One hour after ACTH stimulation all multiple and 53% of the singleton group infants showed a subnormal (, 500 nmol/l, P ¼ 0.007) cortisol response. Two hours after ACTH, nine multiple group patients and 43% of the singletons had subnormal (, 500 nmol/l, P ¼ 0.01) stimulated cortisol levels. Conclusions: We have concluded that VLBW infants from multiple gestations seem to be at an increased risk of insufficient postnatal adrenocortical function. In the future, specific attention should be paid to evaluate further newborn infants from multiple pregnancies with regard to a possible benefit of hydrocortisone substitution in stressful clinical situations.

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In Vivo Evidence for Increased Adrenal Sensitivity to Adrenocorticotropin-(l–24) in the Lamb Fetus Late in Gestation*

Cited by 70 publications

References 16 publications

Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxia during late pregnancy

Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: effects of hypoxia during late pregnancy

Infusion of ACTH stimulates expression of adrenal ACTH receptor and steroidogenic acute regulatory protein mRNA in fetal sheep

Impaired adrenocortical function in very low birth weight infants after multiple pregnancies

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