title: Impact of hormone replacement therapy on endogenous estradiol metabolism in postmenopausal women.
abstract: OBJECTIVE
  Changes in estradiol metabolism may play a role in the pathophysiology of different diseases, of special interest being an increase in D-ring over A-ring metabolites for the risk of breast cancer. In the present work we investigated the effect of exogenous estradiol therapy on endogenous estradiol metabolism in postmenopausal women.
  
  
  METHODS
  Three different studies were carried out in 126 women: in study A the women were treated for 4 weeks either with oral or with transdermal 17beta-estradiol, in study B for 4 weeks with oral or transdermal 17beta-estradiol sequentially combined with oral or transdermal norethisterone acetate, and in study C for 12 weeks either with oral 17beta-estradiol or with an oral continuous combination of 17beta-estradiol with the new progestin dienogest. As main representatives of the A- and D-ring metabolism, 2-hydroxyestrone (2-OHE1) and 16 alpha-hydroxyestrone (16-OHE1), respectively, were measured in 8 h night urine using enzyme immunoassay technique.
  
  
  RESULTS
  Oral estradiol treatment resulted in a significant higher excretion of estradiol metabolites compared to transdermal treatment. Neither oral nor transdermal estradiol induced a significant change in the ratio of 16-OHE1 to 2-OHE1. The addition of oral or transdermal norethisterone acetate to estradiol did not alter on average the endogenous estradiol metabolism, although in individual patients a significant increase in 16-OHE1 metabolism was observed only with oral norethisterone. The continuous oral addition of dienogest did not lead to any significant change in estradiol metabolism.
  
  
  CONCLUSIONS
  These results indicate that oral estradiol replacement therapy enhances the quantity of circulating estradiol metabolites. This may have a more negative impact on estrogenic target cells as compared to transdermal application. Progestin addition to estradiol replacement therapy seems to have no major impact on endogenous estradiol metabolism. Further studies, however, are necessary to evaluate the progestin effect in possible pre-disposed patients.
authors.affiliation: Department of Obstetrics and Gynecology, Section of Endocrinology and Menopause, University of Tuebingen, Calwerstrasse 7, 72 076, Tuebingen, Germany. endo.meno@med.uni-tuebingen.de
authors.forename: Alfred O
authors.initials: AO
authors.lastname: Mueck
authors.forename: Harald
authors.initials: H
authors.lastname: Seeger
authors.forename: Diethelm
authors.initials: D
authors.lastname: Wallwiener
mesh_terms: D004958:Estradiol / Q000378:metabolism* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D009640:Norethindrone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000077563:Norethindrone Acetate; D017698:Postmenopause
chemical_list: C023635:dienogest; D004958:Estradiol; D009277:Nandrolone; D000077563:Norethindrone Acetate; D009640:Norethindrone