title: Intrauterine release of progesterone antagonist ZK230211 is feasible and results in novel endometrial effects: a pilot study.
abstract: BACKGROUND
  Continuous administration of progesterone antagonists (PAs) results in endometrial suppression and amenorrhoea in several model systems. We compared the effects of intrauterine release of a highly specific PA, ZK230211, to those of a progestin using the levonorgestrel-releasing intrauterine system (LNG-IUS).
  
  
  METHODS
  Forty-two women were randomly fitted with an IUS releasing either ZK230211 at a rate 1, 4 or 8 microg/24 h (ZK-IUS) or LNG (at 20 microg/24 h, LNG-IUS) at 4-8 weeks before hysterectomy. Bleeding patterns, endometrial morphology and content of ZK230211, and various immunohistochemistries (IHCs) were evaluated.
  
  
  RESULTS
  Days of bleeding and spotting were unchanged by the use of ZK-IUSs but were increased by LNG-IUS (P < 0.01). ZK230211 was measurable in all endometrial specimens. Endometrium was partly suppressed in 9-30% of women following the use of ZK-IUSs, and in 67% after LNG-IUS. IHCs for Ki-67 and phosphorylated histone H3 were not suggestive of proliferative activity in any group. Compared to LNG, progesterone receptor (PR) was increased following ZK230211 in surface epithelium (all three doses P < 0.01-P < 0.05) and stroma at 4 microg/24 h (P < 0.05). Although low, androgen receptor staining was higher in endothelial epithelium following LNG than ZK230211 (P < 0.05). Insulin-like growth factor-binding protein-1 (IGFBP-1) was detectable only following LNG (P < 0.0001).
  
  
  CONCLUSIONS
  Short-term intrauterine release of ZK230211 did not change bleeding patterns or result in endometrial suppression. Expression of proliferation markers was low following the use of both IUSs. Absence of IGFBP-1 and increase in PR reflect the PA effects of ZK230211.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Helsinki, PO Box 140, SF-00029 HUS, Helsinki, Finland. oskari.heikinheimo@helsinki.fi
authors.forename: Oskari
authors.initials: O
authors.lastname: Heikinheimo
authors.forename: Susheel
authors.initials: S
authors.lastname: Vani
authors.forename: Olli
authors.initials: O
authors.lastname: Carpén
authors.forename: Annamaija
authors.initials: A
authors.lastname: Tapper
authors.forename: Päivi
authors.initials: P
authors.lastname: Härkki
authors.forename: Eeva-Marja
authors.initials: EM
authors.lastname: Rutanen
authors.forename: Hilary
authors.initials: H
authors.lastname: Critchley
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis; D049109:Cell Proliferation; D016503:Drug Delivery Systems; D004717:Endometrium / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D004727:Endothelium / Q000737:chemistry; D004963:Estrenes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000032:analysis; D019394:Ki-67 Antigen / Q000032:analysis; D008595:Menorrhagia / Q000188:drug therapy*; D008875:Middle Aged; D011374:Progesterone / Q000037:antagonists & inhibitors*; D011980:Receptors, Progesterone / Q000032:analysis / Q000037:antagonists & inhibitors; D005466:Fluorocarbons
chemical_list: D015415:Biomarkers; D004963:Estrenes; D018970:Insulin-Like Growth Factor Binding Protein 1; D019394:Ki-67 Antigen; D011374:Progesterone; D011980:Receptors, Progesterone; C032231:IGFBP1 protein, human; C419162:lonaprisan; D005466:Fluorocarbons