Activation of the Fetal Hypothalamic-Pituitary-Adrenal Axis With Prolonged and Graded Hypoxemia

Abstract

Objective: The purpose of this study was to determine whether activation of the hypothalamic-pituitary-adrenal (HPA) axis and uteroplacental prostaglandin (PG) response occur before metabolic deterioration with a progressive decrease in fetal oxygenation.

Methods: Twenty-one chronically catheterized fetal sheep were studied between 126 and 135 days' gestation during a 24-hour normoxic control period and subsequently during 4 experimental days of either prolonged and graded hypoxemia, induced by progressively lowering the maternal inspired oxygen concentration (induced hypoxia, n = 12), or continued study on room air (control, n = 6; spontaneous hypoxia, n = 3). Fetal arterial blood was sampled daily for blood gases and pH, immunoreactive ACTH, cortisol, and PGE₂. Placental cotyledons were obtained at the end of the experiment for measurement of prostaglandin-H synthase (PGHS) enzymatic activity.

Results: For all hypoxia group measurements, progressive reduction in fetal oxygenation resulted in little change in either plasma ACTH or cortisol until arterial O₂ saturation was close to 30% with metabolic acidosis onsetting. This was in keeping with activation of the HPA axis at this time, because ACTH and cortisol values showed a strong linear correlation (r = 0.77, P < .1). Fetal plasma PGE₂ concentrations and cotyledonary PGHS enzymatic activity, although somewhat higher in the hypoxia group animals, were not changed significantly.

Conclusion: In response to prolonged and graded hypoxemia in the ovine fetus, activation of the HPA axis occurs only when the degree of hypoxemia is pronounced and close to that associated with metabolic deterioration, which may limit the time for any uteroplacental response and the ability to initiate labor.

Keywords

Hypothalamic-pituitary-adrenal axis fetal hypoxemia

Get full access to this article

View all access options for this article.

References

1. Challis JRG , Brooks AN . Maturation and activation of hypothalamic-pituitary adrenal function in fetal sheep. Endocrinol Rev 1989;10:182-204.

2. Liggins GC . Adrenocortical-related maturational events in the fetus. Am J Obstet Gynecol 1977;126:931-941.

3. Challis JRG , Olson DM . Parturition. In: Knobil E , Neill JD , eds. The physiology of reproduction. Vol 2. New York: Raven Press, 1988:2177-2177.

4. Akagi, K. Challis JRG . Threshold of hormonal and biophysical responses to acute hypoxemia in fetal sheep at different gestational ages. Can J Physiol Pharmacol 1990;68:549-555.

5. 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;68:1527-1532.

6. Kitanaka T. Alonso JG , Gilbert RD , Siu BL , Clemons GK , Longo LD . Fetal responses to long-term hypoxemia in sheep. Am J Physiol 1989;256 (Regulatory Integraive Comp Physiol 25):R1348-R1354.

7. Kerr DWR , Castro Ml , Valego NK , Rawashdeh NM , Rose JC . Corticotropin and cortisol response to corticotropin-releasing factor in the chronically hypoxemic ovine fetus. 1992;167:1686-1690.

8. Towell ME , Figueroa J , Markowitz S , Elia B , Nathanielsz P. The effect of mild hypoxemia maintained for twenty-four hours on maternal and fetal glucose, lactate, cortisol, and arginine vasopression in pregnant sheep at 122 to 139 days' gestation. Am J Obstet Gynecol 1987;157:1550-1557.

9. Challis JRG , Richardson BS , Rurak D , Wlodek ME , Patrick JE . Plasma adrenocotropic hormone and cortisol and adrenal blood flow during sustained hypoxemia in fetal sheep. Am J Obstet Gynecol 1986;155:1332-1336.

10.

10. Hooper SB , Coulter CL . Deayton JM , Harding R , Thorburn GD . Fetal endocrine responses to prolonged hypoxia in sheep. Am J Physiol 1990;259 (Regulatory Integrative Comp Physiol 28):R703-R708.

11.

11. Sue-Tang A , Bocking AD , Brooks AN , et al. Effects of restricting uteroplacental blood flow on concentrations of corticotrophin-releasing hormone, adrenocorticotrophim. cortisol, and prostaglandin E2 in the sheep fetus during late pregnancy. Can J Physiol Pharmacol 1992;70:1396-1402.

12.

12. Wood CE , Chen H-G. Acidemia stimulates ACTH, vasopression, and heart rate responses in fetal sheep. Am J Physiol 1989;257 (Regulatory Integrative Comp Physiol 26):R344-R349.

13.

13. Gagnon R , Challis J , Johnston L , Fraher L. Fetal endocrine responses to chronic placental embolization in the late-gestation ovine fetus. Am J Obstet Gynecol 1994;170:929-938.

14.

14. Richardson BS , Carmichael L , Homan J , Patrick JE . electrocortical activity, electroocular activity, and breathing movements in fetal sheep with prolonged and graded hypoxemia. Am J Obstet Gynecol 1992;167:533-538.

15.

15. Adamson SL , Kuipers IM , Olson DM , Umbilical cord occlusion stimulates breathing independent of blood gasses and pH. J Appl Physiol 1991;70:1796-1809.

16.

16. Smieja Z , Zakar T , Walton JC , Olson DM . Prostaglandin endoperoxide synthase kinetics in human amnion before and after labor at term and following preterm labor. Placenta 1993;14:163-175.

17.

17. Powell WS . Rapid extraction of arachidonic acid metabolites from biological samples using decyisilyl silica. In: Lands WE , Smith WL , eds. Methods in enzymology. New York: Academic Press, 1982;467-477.

18.

18. Olson DM , Lye SJ , Skinner K , Challis JRG . Early changes in prostaglandin concentrations in ovine maternal and fetal plasma amniotic fluid and from dispersed cell of intrauterine tissue before the onset of ACTH-induced preterm labor. J Reprod Fertil 1984;71:45-55.

19.

19. Langlois DA , Fraher LJ , Khalil MW , Frser M , Challis JRG . Preferential increase in prostaglandin endoperoxide H synthase compared with lipoxygenase activity in sheep placenta and amnion at term pregnancy and after intrafetal glucocorticoid administration. J Endocrinol 1993;139:195-204.

20.

20. Rice GE , Wong MH , Thorburn GD . Gestational changes in prostaglandin synthase activity of ovine cotyledonary microsomes. J Endocrinol 1988;118:265-270.

21.

21. Murotsuki J , Challis JRG , Johnston L , Gagnon R. Increased fetal plasma prostaglandin E2 concentrations during fetal placental embolization in pregnant sheep. Am J Obstet Gynecol 1995;173:30-35.

22.

22. Thorburn GD , Hooper SB , Rice GE , Fowden AL . In: McNellis D , Challis J , Macdonald P , Nathanielsz P , Roberts J , eds. The onset of labor: Cellular and integrative mechanisms. Ithaca, New York: Perinatology Press, 1988:185-185.

23.

23. Wimsatt J , Nathanielsz PW , Sirois J. Induction of prostaglandin endoperoxide synthase isoform-2 in ovine cotyledonary tissue during late gestation. Endocrinol 1993;133:1068-1073.

24.

24. Gagnon R , Webster K , Campbell K , Natale R , Milne K. A comparison of gestational-age specific perinatal mortality between appropriate-for-gestational-age and small-for-gestational-age singleton fetuses and newborns. Society of Obstetricians and Gynaecologists of Canada, Abstract S08, 1993.

25.

25. van Vliet MAT , Martin CB , Nijuis JG , Prechtl HFR . The relationship between fetal activity and behavioral states and fetal breathing movements in normal and growth-retarded fetuses. Am J Obstet Gynecol 1985;153:582-588.

26.

26. Gagnon R , Hunse C , Fellows F , Carmichael L , Patrick J. Fetal heart rate and activity patterns in growth-retarded fetuses: Changes after vibroacoustic stimulation. Am J Obstet Gynecol 1988;158:265-271.