Abstract
Objective
This study was designed to determine the effect of umbilical cord occlusion (UCO) on fetal endocrine responses in the long-term hypoxemic (LTH) ovine fetus.
Methods
Pregnant ewes were maintained at high altitude (3820 m) from day 30 of gestation. Normoxic control and LTH fetuses were catheterized, and an inflatable occluder was placed on the umbilical cord at day 132 of gestation. In the LTH group, maternal oxygen tension was maintained at approximately 60 mmHg by nitrogen infusion through a maternal tracheal catheter. On day 137, two 5-minute UCOs were performed. On day 139, the study was repeated with a 10-minute UCO.
Results
Basal adrenocorticotropic hormone (ACTH) levels and peak responses to the first 5-minute UCO were not different between control and LTH fetuses (17.6 ± 4.0 to 418.8 ± 41.3 in controls, 25.7 ± 4.0 to 530.0 ± 93. Opg/mL in LTH fetuses). A similar pattern was observed during the second UCO. Basal Cortisol levels were similar in both groups. In response to UCO, a significant increase in Cortisol was observed in both groups, but peak concentrations in the LTH group were significantly higher than those in the control group (23.9 ±4.8 versus 14.8 ± 2.9 ng/mL, respectively, P <.05). The second occlusion also increased Cortisol concentrations, but no differences were observed between groups. After the 10-minute UCO, the ACTH and Cortisol responses were similar to the first 5-minute occlusion, with higher Cortisol levels in the LTH fetuses.
Conclusion
Despite similar ACTH responses to UCO, the Cortisol response was greater in the LTH fetuses than in normoxic controls. LTH appears to result in enhanced adrenal sensitivity to a secondary stressor or altered Cortisol metabolism. (J Soc Gynecol Investig 2004; 11:131-40)
Similar content being viewed by others
References
Gu W, Jones CT, Parer JT. Metabolic and cardiovascular effects on fetal sheep of sustained reduction of uterine blood flow. J Physiol 1985;368:109–29.
Jones CT, Robinson RO. Plasma catecholamines in fetal and adult sheep. J Physiol 1975;248:15–33.
Rurak DW. Plasma vasopressin levels during hypoxemia and the cardiovascular effects of exogenous vasopressin in foetal and adult sheep. J Physiol 1978;277:341–57.
Bocking AD, McMillen IC, Harding R, Thorburn GD. Effect of reduced uterine blood flow on fetal and maternal Cortisol. J Dev Physiol 1986;8:237–45.
Boddy K, Jones CT, Mantnell C, Ratcliffe JG, Robinson JS. Changes in plasma ACTH and corticosteroid of the maternal and fetal sheep during hypoxia. Endocrinology 1974;94:588–91.
Reid DL, Parer JT, Williams K, Darr D, Phernetton TM, Rankin JH. Effects of severe reduction in maternal placental blood flow on blood flow distribution in the sheep fetus. J Dev Physiol 1991;15(3):183–8.
Giussani DA, Spencer JA, Moore PJ, Bennet L, Hanson MA. Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep. J Physiol 1993;461:431–49.
Gardner DS, Fletcher AJ, Fowden AL, Giussani DA. Plasma adrenocorticotropin and Cortisol concentrations during acute hypoxemia after a reversible period of adverse intrauterine conditions in the ovine fetus during late gestation. Endocrinology 2001;142(2):589–98.
Cohn HE, Sacks EJ, Heymann MA, Rudolph AM. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol 1974;120:817–24.
Giussani DA, McGarrigle HH, Moore PJ, Bennet L, Spencer J AD, Hanson MA. Carotid sinus nerve section and the increase in plasma Cortisol during acute hypoxia in fetal sheep. J Physiol 1994;477(1):75–80.
Akagi K, Challis JRG. Hormonal and biophysical responses to acute hypoxemia in fetal sheep at 0.7-0.8 gestation. Can J Physiol Pharmacol 1990;68:1527–32.
Wilkening PJB, Meschia G. Fetal oxygen uptake, oxygenation, and acid-base balance as a function of uterine blood flow. Am J Physiol 1983;244:H749-H755.
Itskovitz J, LaGamma EF, Rudolph AM. Heart rate and blood pressure responses to umbilical cord compression in fetal lambs with special reference to the mechanism of variable deceleration. Am J Obstet Gynecol 1983;147:451–7.
Giussani DA, Unno N, Jenkins SL, et al. Dynamics of cardio-vascular responses to repeated partial umbilical cord compression in late-gestation sheep fetus. Am J Physiol 1997;273(5 Pt 2): H2351–H2360.
Unno N, Giussani DA, Man WKH, et al. Changes in adreno-corticotropin and Cortisol responsiveness after repeated partial umbilical cord occlusions in the late gestation ovine fetus. Endocrinology 1997;138:259–63.
Green LR, Kawagoe Y, Fraser M, Challis JR, Richardson BS. Activation of the hypothalamic-pituitary-adrenal axis with repetitive umbilical cord occlusion in the preterm ovine fetus. J Soc Gynecol Investig 2000;7(4):224–32.
Gardner DS, Fletcher AJ, Fowden AL, Giussani DA. A novel method for controlled and reversible long term compression of the umbilical cord in fetal sheep. J Physiol 2001;535:217–29.
Gagnon R, Murotsuki J, Challis JR, Fraher L, Richardson BS. Fetal sheep endocrine responses to sustained hypoxemic stress after chronic fetal placental embolization. Am J Physiol 1997; 272(5 Pt 1):E817–23.
Phillips ID, Simonetta G, Owens JA, Robinson JS, Clarke IJ, McMillen C. Placental restriction alters the functional develop-ment of the pituitary-adrenal axis in the sheep fetus during late gestation. Pediatr Res 1996;40:861–6.
Harvey LM, Gilbert RD, Longo LD, Ducsay CA. Changes in ovine fetal adrenocortical responsiveness after long-term hypoxemia. Am J Physiol 1993;264:E741-7.
Dale PS, Ducsay CA, Gilbert RD, Koos BJ, Longo LD, Power GG. A microcomputer program for real time data acquisition in the perinatal physiology laboratory. J Dev Physiol 1989;11:56–61.
Apostalakis EM, Longo LD, Yellon SM. Regulation of basal adrenocorticotropin and Cortisol secretion by arginine vasopressin in the fetal sheep during late gestation. Endocrinology 1991;129:295–300.
Wood CE. Sinoaortic denervation attenuates the reflex responses to hypotension in fetal sheep. Am J Physiol 1989;256:R1103-R1110.
Giussani DA, McGarrigle HH, Spencer JAD, Moore PJ, Bennet L, Hanson MA. Effect of carotid denervation on plasma vasopressin levels during acute hypoxia in the late-gestation sheep fetus. J Physiol 1994;477(1):81–7.
Green LR, McGarrigle HH, Bennet L, Hanson MA. The effect of acute hypoxemia on plasma angiotensin II in intact and carotid sinus-denervated fetus sheep. J Physiol 1994;476(P):81P.
Giussani DA, Spencer JAD, Hanson MA. Fetal cardiovascular reflex responses to hypoxaemia. Fet Mat Med Rev 1994;6:17–37.
Itskovitz J, Rudolph AM. Denervation of arterial chemorecep-tors and baroreceptors is fetal lambs in utero. Am J Physiol 1982;242:H543-8.
Itskovitz J, LaGamma EF, Bristow J, Rudolph AM. Cardiovas-cular responses to hypoxemia in sino-aortic denervated fetal sheep. Pediatr Res 1991;30:381–5.
Wood CE, Cheung CY, Brace PJ. Fetal heart rate, arterial pressure, and blood volume responses to Cortisol infusion. Am J Physiol 1987;253:R904-9.
Docherty CC, Kalmar-Nagy J, Engelen M, et al. Effect of in vivo fetal infusion of dexamethasone at 0.75 GA on fetal ovine resistance artery responses to ET-1. Am J Physiol Regul Integr Comp Physiol 2001;281(1):R261-8.
Forhead AJ, Broughton PF, Fowden AL. Effect of Cortisol on blood pressure and the renin-angiotensin system in fetal sheep during late gestation. J Physiol 2000;526 Pt 1:167–76.
Rose JC, Meis PJ, Morris M. Ontogeny of endocrine (ACTH, vasopressin, Cortisol) responses to hypotension in lamb fetuses. Am J Physiol 1981;240:E656–61.
Wood CE, Chen HG, Bell ME. Role of vagosympathetic fibers in the control of adrenocorticotropic hormone, vasopressin, and renin responses to hemorrhage in fetal sheep. Circ Res 1989;64:515–23.
Chen HG, Wood CE. Reflex control of fetal arterial pressure and hormonal responses to slow hemorrhage. Am J Physiol 1992;262: H225-33.
Akagi K, Berdusco ETM, Challis JRG. Cortisol inhibits the ACTH but not AVP response to hypoxemia in fetal lambs at day 123-128 of gestation. J Dev Physiol 1990;14:319–24.
Wood CE, Keil LC, Rudolph AM. Hormonal and hemodynamic responses to vena caval obstruction in fetal sheep. Am J Physiol 1982;243(4):E278-86.
Wood CE, Chen HG. Acidemia stimulates ACTH, vasopressin, and heart rate responses in fetal sheep. Am J Physiol 1989;257(2 Pt 2):R344–9.
Krieger DT, Liotta AS, Hauser H, Brownstein MJ. Effect of stress, adrenocorticotropin or corticosteroid treatment, adrenal-ectomy, or hypophysectomy on hypothalamic immunoreactive adrenocorticotropin concentrations. Endocrinology 1979; 105(3):737–42.
Myers DA, Robertshaw D, Nathanielsz PW. Effect of bilateral splanchnic nerve section on adrenal function in the ovine fetus. Endocrinology 1990;127:2328–35.
Riquelme RA, Llanos JA, McGarrigle HH, Sanhueza EM, Hanson MA, Giussani DA. Chemoreflex contribution to adrenocortical function during acute hypoxemia in the llama fetus at 0.6 to 0.7 of gestation. Endocrinology 1998;139:2564–70.
Kamitomo M, Alonso JG, Okai T, Longo LD, Gilbert RD. Effects of long-term, high-altitude hypoxemia on ovine fetal cardiac output and blood flow distribution. Am J Obstet Gynecol 1993;169:701–7.
Fraser M, Braems GA, Challis JR. Developmental regulation of corticotrophin receptor gene expression in the adrenal gland of the ovine fetus and newborn lamb: Effects of hypoxia during late pregnancy. J Endocrinol 2001;169(1):1–10.
Penninga L, Longo LD. Ovine placentome morphology: Effect of high altitude, long-term hypoxia. Placenta 1998; 19(2–3): 187–93.
Monder C. The forms and functions of 11 P-hydorxysteroid dehydrogenase. J Steroid Biochem Mol Biol 1993;45:161–5.
White PC, Mime T, Agarwal AK. 11B-Hydroxysteroid dehy-drogenase and the syndrome of apparent minerlocorticoid excess. EndocrRev 1997;18:135–56.
Yang K, Yu M. Evidence for distinct isoforms of 11 beta-hydroxysteroid dehydrogenase in the ovine liver and kidney. J Steroid Biochem Mol Biol 1994;49(2–3):245–50.
Murotsuki J, Gagnon R, Pu X, Yang K. Chronic hypoxemia selectively down-regulates 11 beta-hydroxysteroid dehydrogenase type 2 gene expression in the fetal sheep kidney. Biol Reprod 1998;58(1):234–9.
Clarke KA, Ward JW, Forhead AJ, Giussani DA, Fowden AL. Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal Cortisol. J Endocrinol 2002;172(3):527–34.
Stewart PM, Whorwood CB, Mason JI. Type 2 11 beta-hydrox-ysteroid dehydrogenase in foetal and adult life. J Steroid Biochem Mol Biol 1995;55(5–6):465–71.
Cheung CY. Enhancement of adrenomedullary catecholamine release by adrenal cortex in fetus. Am J Physiol 1984;247:E693-7.
Cheung CY. Direct adrenal medullary catecholamine response to hypoxia in fetal sheep. J Neurochem 1989;52(1):148–53.
Cheung CY. Fetal adrenal medulla catecholamine response to hypoxia-direct and neural components. Am J Physiol 1990;258(6 Pt 2):R1340–6.
Stein PE, White SE, Homan J, et al. Fetal endocrine responses to prolonged reduced uterine blood flow are altered following bilateral sectioning of the carotid sinus and vagus nerves. J Endocrinol 1998;157(1):149–55.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by National Institutes of Health grant HD 31226.
Rights and permissions
About this article
Cite this article
Imamura, T., Umezaki, H., Kaushal, K.M. et al. Long-Term Hypoxia Alters Endocrine and Physiologic Responses to Umbilical Cord Occlusion in the Ovine Fetus. Reprod. Sci. 11, 131–140 (2004). https://doi.org/10.1016/j.jsgi.2003.09.006
Published:
Issue Date:
DOI: https://doi.org/10.1016/j.jsgi.2003.09.006