Archives of gynecology

, Volume 231, Issue 4, pp 315–320 | Cite as

Importance of catecholestrogens in the regulation of the ovarian cycle

  • P. Ball
  • G. Emons
  • R. Knuppen


Using highly stabilized catecholestrogen preparations-ascorbic acid added to the free alcohols or benzoic acid derivatives — 2- and 4-hydroxyestrogens were tested in simple, clearly defined animal models: As index for the peripheral action the influence on vaginal opening and uterus weight gain was monitored after continuous s.c. administration for 6 days (minipumps) in immature intact rats resulting in a relative estrogenic potency (estradiol = 100%) of 70–100% for 4-hydroxyestradiol and less than 30% for 2-hydroxyestradiol. As index for the central action LH levels were measured in adult ovx rats leading to the same relations in the relative potencies. As index for both central and peripheral actions LH levels and the formation of corpora lutea were investigated in animals with an intact but prepubertal feed-back loop, i.e. in 25-day-old immature rats. 4-Hydroxyestradiol in this model clearly triggered LH surges and induced ovulations, its potency being in the same range as that of estradiol. 2-Hydroxyestradiol, in comparable doses, again showed no significant effect. Finally, female immature animals known to ovulate 3 days after PMS injection were treated concomitantly with either primary or catecholestrogen-antibody preparations. Whereas the primary estrogen antibody significantly blocked ovulation, the 2- and 4-hydroxyestrogen antibodies were ineffective. If, however, PMS and estrogen-antibody treated animals were supplemented with 4-hydroxyestrogens, ovulations could be restored. Thereby, it was inferred that peripheral 4-hydroxyestrogens, though not essential for the physiology of reproduction, can completely replace the physiologically essential peripheral estradiol at central target sites.

Key words

Ovarian cycle Physiology Catecholestrogens Rat 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ball P, Knuppen R (1978) Formation of 2- and 4-hydroxyestrogens by brain, pituitary and liver of the human fetus. J Clin Endocrinol Metab 47: 732–737PubMedGoogle Scholar
  2. Ball P, Knuppen R (1980) Catecholestrogens (2- and 4-hydroxyestrogens): Chemistry, biogenesis, metabolism, occurrence and physiological significance. Acta Endocrinol [Suppl] (Copenh) 232: 1–128Google Scholar
  3. Ball P, Haupt M, Knuppen R (1978) Comparative studies on the metabolism of oestradiol in the brain, the pituitary and the liver of the rat. Acta Endocrinol (Copenh) 87: 1–11Google Scholar
  4. Ball P, Emons G, Gethmann U (1981a) Effect of low doses of continuously administered catecholoestrogens on peripheral and central target organs. Acta Endocrinol (Copenh) 96: 470–474Google Scholar
  5. Ball P, Emons G, Klingebiel T, Grühn K-M, Knuppen R (1981b) Effect of catecholoestrogens on luteinizing hormone levels in long-term ovariectomized adult rats. Endocrinology 109: 1037–1039PubMedGoogle Scholar
  6. Ball P, Schwarzlose C, Emons G (1982) Effects of antibodies to catecholoestrogens and catecholoestrogen-methyl ethers on PMS induced ovulations in immature rats. Acta Endocrinol (Copenh) 99: 443–447Google Scholar
  7. Caligaris L, Astrada JJ, Taleisnik S (1971) Biphasic effects of progesterone on the release of gonadotrophin in rats. Endocrinology 89: 331–337PubMedGoogle Scholar
  8. Emons G, Ball P (1981) Induction of ovulation in immature female rats by a single injection of 4-hydroxyoestradiol-benzoate. Acta Endocrinol (Copenh) 240: 101–102Google Scholar
  9. Emons G, Hoppen H-O, Ball P, Knuppen R (1980) 4-Hydroxyestrone, isolation and identification in human urine. Steroids 36: 73–79CrossRefPubMedGoogle Scholar
  10. Emons G, Mente C, Knuppen R, Ball P (1981) Radioimmunoassay of 4-hydroxyoestrone in human urine. Acta Endocrinol (Copenh) 97: 251–257Google Scholar
  11. Ferin M, Zimmering E, van de Wiele RL (1969) Effects of antibodies to oestradiol-17β on PMS-induced ovulations in immature rats. Endocrinology 84: 893–900PubMedGoogle Scholar
  12. Franks S, Ball P, Naftolin F, Ruf KB (1980) Effect of catecholoestrogens on induced ovulation of the immature rat. J Endocrinol 86: 263–268PubMedGoogle Scholar
  13. Gethmann U, Knuppen R (1976) Effect of 2-hydroxyestrone on lutropin (LH) and follitropin (FSH) secretion in the ovariectomized rat. Hoppe Seylers Z Physiol Chem 357: 1011–1013PubMedGoogle Scholar
  14. Hohlweg W (1934) Veränderungen des Hypophysenvorderlappens und des Ovariums nach Behandlung mit großen Dosen von Follikelhormon. Klin Wochenschr 13: 92–95CrossRefGoogle Scholar
  15. Legan SJ, Coon GA, Karsch FJ (1975) Role of estrogen as initiator of daily LH-surges in the ovariectomized rat. Endocrinology 96: 50–56PubMedGoogle Scholar
  16. Martucci C, Fishman J (1976) Uterine estrogen receptor binding of catecholestrogens and estetrol. Steroids 27: 325–333CrossRefPubMedGoogle Scholar
  17. Martucci C, Fishman J (1979) Impact of continuously administered catechol estrogens on uterine growth and luteinizing hormon secretion. Endocrinology 105: 1288–1292PubMedGoogle Scholar
  18. Naftolin F, Morishita H, Davies IJ, Todd R, Ryan KJ, Fishman F (1975) 2-Hydroxyestrone induced rise in serum luteinizing hormone in the immature male rat. Biochim Biophys Res Commun 64: 905–910CrossRefGoogle Scholar
  19. Puig-Duran E, MacKinnon PCB (1978) A critical period for the positive feedback effect in immature (21-day-old) rats. J Endocrinol 76: 311–320PubMedGoogle Scholar
  20. Rodriguez-Sierra JF, Blake CA (1980) Lack of stimulation of phasic LH release by catechol estrogens in the rat. Life Sci 26: 743–748CrossRefPubMedGoogle Scholar

Copyright information

© J. F. Bergmann Verlag 1982

Authors and Affiliations

  • P. Ball
    • 1
  • G. Emons
    • 1
  • R. Knuppen
    • 1
  1. 1.Arbeitsgruppe Klinische EndokrinologieInstitut für Biochemische Endokrinologie, Medizinische Hochschule LübeckLübeckFederal Republic of Germany

Personalised recommendations