Hum. Reprod. Advance Access published online on July 17, 2007
Human Reproduction, doi:10.1093/humrep/dem235
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Intrauterine release of progesterone antagonist ZK230211 is feasible and results in novel endometrial effects: a pilot study
1 Department of Obstetrics and Gynaecology, University of Helsinki, PO Box 140, SF-00029 HUS, Helsinki, Finland 2 Division of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, UK 3 Department of Pathology, University of Turku, Turku, Finland
4 Correspondence address. Tel: +358-50-4271533; Fax: +358-9-47174801; E-mail: oskari.heikinheimo{at}helsinki.fi
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 µg/24 h (ZK-IUS) or LNG (at 20 µg/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 µg/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.
Key words: progesterone antagonist/endometrium/insulin-like growth factor-binding protein-1/levonorgestrel/ZK230211
Equal senior contribution by authors O.H. and H.C. Submitted on April 20, 2007; resubmitted on June 20, 2007; accepted on June 25, 2007.