, Volume 6, Issue 3, pp 271–278 | Cite as

The effects of estradiol-17° infusion into fetal sheep in late gestation

  • Sheila Wang
  • Stephen G. Matthews
  • Treena M. Jeffray
  • M. Yvette Stevens
  • Kaiping Yang
  • Geoffrey L. Hammond
  • John R. G. Challis
Original Articles


Activation of the hypothalamic-pituitary-adrenal (HPA) axis of fetal sheep during late gestation is associated with increases in plasma concentrations of adrenocorticotropic hormone (ACTH) and cortisol, and ultimately results in parturition. However, the mechanisms contributing to the concurrent increases in ACTH and cortisol are unclear. Plasma estradiol-17β (E2) concentrations increase progressively in the prepartum ovine fetus, and we hypothesized that E2 may influence HPA activity by affecting either basal and/or hypoxemia-stimulated ACTH release. We examined potential mechanisms, including altered expression of pro-opiomelanocortin (POMC) in fetal pituitary corticotrophs, and changes in corticosteroid binding globulin (CBG) and/or the enzymes 11β hydroxy steroid dehydrogenase (11β HSD)-1 or 11β HSD-2 in liver and placenta, that could alter negative feedback control. We infused fetal sheep at 127 d of gestation with either E2 (100 μg/24 h) or saline for 100 h. Fetal arterial blood samples were collected at 8 h intervals during the infusion of E2 or saline (n=4), for measurement of basal plasma ACTH and cortisol concentrations, as well as plasma corticosteroid binding capacity (CBC). Placenta and fetal liver samples were collected at 100 h for measurement of placental 11 β HSD-1 and 11β HSD-2 mRNA and hepatic CBG and 11β HSD-1 mRNA, by Northern blotting. Fetal pituitary samples were collected for measurement of POMC mRNA byin situ hybridization. In a separate experiment, fetuses were exposed to 2 h of hypoxemia at 75 h of E2 or saline infusion (n=4), and fetal arterial blood samples were collected during the period of hypoxemia for measurement of plasma ACTH and cortisol concentrations. E2 infusion had no effect on basal plasma concentrations of ACTH or total cortisol, or on the stimulated levels of ACTH or total cortisol achieved in response to hypoxemia. Basal fetal pituitary POMC mRNA also did not change significantly with E2 infusion. No significant increases were observed in plasma CBC during E2 administration. However, hepatic CBG and 11β HSD-1 mRNA were significantly elevated in the livers of E2-treated fetuses. Placental 11β HSD-1 mRNA; but not 11β HSD-2 mRNA was increased by E2 treatment. These data do not support a direct effect of exogenous E2 at the level of basal or hypoxemia-stimulated ACTH output, but suggest that elevated E2 concentrations may alter the expression of genes encoding proteins implicated in tonic regulation of fetal HPA function.

Key Words

Estradiol sheep fetus adrenocorticotropin cortisol corticosteroid binding globulin 11β hydroxysteroid dehydrogenase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Brooks, A. N., Currie, I. S., Gibson, F., and Thomas, G. B. (1992).J. Reprod. Fert.,Suppl. 45, 69–84.Google Scholar
  2. 2.
    Challis, J. R. G. and Brooks, A. N. (1989).Endocrine Reviews 10, 182–204.PubMedCrossRefGoogle Scholar
  3. 3.
    Handa, R. J., Burgess, L. H., Kerr, J. E., and O'Keefe, J. A. (1994).Horm. and Behav. 28, 464–476.CrossRefGoogle Scholar
  4. 4.
    Carey, M. P., Deterd, C. H., de Koning, J., Helmerhorst, F., and de Kloet, E. R. (1995).J. Endocr. 144, 311–321.PubMedCrossRefGoogle Scholar
  5. 5.
    Kitay, J. I. (1961).Endocrinology 68, 818–824.PubMedCrossRefGoogle Scholar
  6. 6.
    Gemzell, C. A. (1952).Acta Endocr. (Copenh.) 11, 221–228.Google Scholar
  7. 7.
    Viau, V. and Meaney, M. J. (1991).Endocrinology 129, 2503–2511.PubMedCrossRefGoogle Scholar
  8. 8.
    Challis, J. R. G. and Patrick, J. E. (1981).Can. J. Physiol. Pharmacol. 59, 970–978.PubMedCrossRefGoogle Scholar
  9. 9.
    Robertson, H. A. and Smeaton, T. C. (1973).J. Reprod. Fert. 35, 461–468.CrossRefGoogle Scholar
  10. 10.
    Saoud, C., Kelleman, A., and Wood, C. E. (1994). Society of Gynecological Investigation Meeting, p. 405, Abstract 397.Google Scholar
  11. 11.
    Yang, K. (1995).Endocr. Res. 21, 367–377.PubMedCrossRefGoogle Scholar
  12. 12.
    Challis, J. R. G., Harrison, F. A., and Heap, R. B. (1973).J. Endocr. 57, 97–110.PubMedCrossRefGoogle Scholar
  13. 13.
    Wood, C. E. and Saoud, C. J. (1996). 10th International Congress of Endocrinology June 12–15, p. 862, Abstract P3-429.Google Scholar
  14. 14.
    Burgess, L. H., and Handa, R. J. (1992).Endocrinology 131, 1261–1269.PubMedCrossRefGoogle Scholar
  15. 15.
    Grino, M., Hery, M., Paulmyer Lacroix, O., and Anglade, G. (1995). The Endocrine Society 77th Annual Meeting, Abstract P1-574.Google Scholar
  16. 16.
    Treiser, S. L. and Wardlaw, S. L. (1992).Neuroendocrinology 55, 167–173.PubMedCrossRefGoogle Scholar
  17. 17.
    Pelletier, G. (1993).Ann. NY Acad of Sci. 680, 246–259.CrossRefGoogle Scholar
  18. 18.
    Broad, K. D., Kendrick, K. M., Sirinathsinghi, D. J. S., and Keverne, E. B. (1993).J. Neuroendocrinology 5, 711–719.CrossRefGoogle Scholar
  19. 19.
    Challis, J. R. G., Berdusco, E. T. M., Jeffray, T. M., Yang, K., and Hammond, G. L. (1995).J. Steroid Biochem. & Mol. Bio. 53, 523–527.CrossRefGoogle Scholar
  20. 20.
    Ballard, P. L. (1979). In:Glucocorticoid Hormone Action. Monographs in Endocrinology. Baxter, J. D. and Rousseau, G. G. (eds.). Springer-Verlag: Berlin.Google Scholar
  21. 21.
    Brien, T. G. (1981).Clin. Endocr. 14, 193–212.PubMedCrossRefGoogle Scholar
  22. 22.
    Coolens, J-L., Van Baelen, H., and Heyns, W. (1987).J. Steroid Biochem. 26, 197–202.PubMedCrossRefGoogle Scholar
  23. 23.
    Lindholm, J. and Schultz Moller, N. (1973).Scand. J. Clin. Lab. Invest. 31, 119–122.PubMedCrossRefGoogle Scholar
  24. 24.
    Moore, D. E., Kawagoe, S., Davajan, V., Mishell, D. R., and Nakamura, R. M. (1978).Am. J. Obstet. Gynecol. 130, 475–481.PubMedGoogle Scholar
  25. 25.
    Ballard, P. L., Kitterman, J. A., Bland, R. D., Clyman, R. I., Gluckman, P. D., Platzker, A. C., Kaplan, S. L., and Grumbach, M. M. (1982).Endocrinology 110, 359–366.PubMedCrossRefGoogle Scholar
  26. 26.
    Challis, J. R. G., Nancekievill, E. A., and Lye, S. J. (1985).Endocrinology 116, 1139–1144.PubMedCrossRefGoogle Scholar
  27. 27.
    Hammond, G. L. (1990).Endocr. Rev. 11, 65–79.PubMedCrossRefGoogle Scholar
  28. 28.
    Berdusco, E. T. M., Yang, K., Hammond, G. L., and Challis, J. R. G. (1995).J. Endocr. 146, 121–130.PubMedCrossRefGoogle Scholar
  29. 29.
    Yang, K., Langlois, D. A., Campbell, L. E., Challis, J. R. G., Krkosek, M., and Yu, M. Placenta, in press.Google Scholar
  30. 30.
    Berdusco, E. T. M., Milne, W. K., and Challis, J. R. G. (1994).J. Endocr. 140, 425–430.PubMedCrossRefGoogle Scholar
  31. 31.
    Pepe, G. J., Waddell, B. J., Stahl, S. J., and Albrecht, E. D. (1988).Endocrinology 122, 78–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Baggia, S., Albrecht, E. D., and Pepe, G. J. (1990).Endocrinology 126, 2742–2748.PubMedCrossRefGoogle Scholar
  33. 33.
    Pepe, G. J., Davies, W. A., and Albrecht, E. D. (1994).Endocrinology 135, 2581–2587.PubMedCrossRefGoogle Scholar
  34. 34.
    Pepe, G. J., Waddell, B. J., and Albrecht, E. D. (1990).Endocrinology 127, 3117–3123.PubMedCrossRefGoogle Scholar
  35. 35.
    Akagi, K., and Challis, J. R. G. (1990).Can. J. Physiol. Pharmacol. 68, 549–555.PubMedCrossRefGoogle Scholar
  36. 36.
    Challis, J. R. G., Richardson, B. S., Rurak, D., Wlodek, M. E., and Patrick, J. E. (1986).Am. J. Obstet. Gynecol. 155, 1332–1336.PubMedGoogle Scholar
  37. 37.
    Norman, L. J., Lye, S. J., Wlodek, M. E., and Challis, J. R. G. (1985).Can. J. Physiol. Pharmacol. 63, 1398–1403.PubMedCrossRefGoogle Scholar
  38. 38.
    Matthews, S. G., Han, X., Lu, F., and Challis, J. R. G. (1994).J Mol. Endocrinology 13, 175–185.CrossRefGoogle Scholar
  39. 39.
    Yang, K., Matthews, S. G., and Challis, J. R. G. (1995).J. Mol. Endocrinology 14, 109–116.CrossRefGoogle Scholar
  40. 40.
    Gossard, F. J., Chang, A. C. Y., and Cohen, S. N. (1986).Biochim. Biophys. Acta 866, 68–74.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 1997

Authors and Affiliations

  • Sheila Wang
    • 1
    • 3
  • Stephen G. Matthews
    • 1
    • 2
  • Treena M. Jeffray
    • 1
  • M. Yvette Stevens
    • 1
  • Kaiping Yang
    • 3
    • 5
    • 6
  • Geoffrey L. Hammond
    • 4
    • 5
    • 7
  • John R. G. Challis
    • 1
    • 2
    • 3
    • 6
  1. 1.Department of PhysiologyUniversity of TorontoToronto
  2. 2.Department of Obstetrics and GynecologyUniversity of TorontoToronto
  3. 3.Department of PhysiologyUniversity of Western OntarioCanada
  4. 4.Department of Pharmacology and ToxicologyUniversity of Western OntarioCanada
  5. 5.Department of Obstetrics and GynecologyUniversity of Western OntarioCanada
  6. 6.Lawson Research InstituteLondon
  7. 7.London Regional Cancer CentreLondon

Personalised recommendations