Human Reproduction, Vol. 18, No. 12, 2610-2617,
December 2003
© 2003 European Society of Human Reproduction and Embryology
Local levonorgestrel regulation of androgen receptor and 17
-hydroxysteroid dehydrogenase type 2 expression in human endometrium
1 Centre for Reproductive Biology, Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, 2 Department of Oncology, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK and 3 Division of Reproductive Sciences, Oregon Regional Primate Centre, 505 NW 185th Avenue, Beaverton, OR 97006, USA
4 To whom correspondence should be addressed. e-mail: Hilary.Critchley{at}ed.ac.uk
BACKGROUND: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, unscheduled breakthrough bleeding (BTB), leads to discontinuation in a proportion of users. The LNG-IUS down-regulates endometrial progesterone and estrogen receptors and this may play a role in the mechanism responsible for BTB. LNG is an androgenic progestogen and so we examined the regulation of the androgen receptor (AR) in endometrium exposed to intrauterine LNG. Furthermore, as the enzyme 17
-hydroxysteroid dehydrogenase type 2 (17HSD2) regulates intracellular levels of estrogens, progestins and androgens, we evaluated the changes in expression of 17HSD2 in the same tissue endometrial samples. METHODS: Immunohistochemistry and real time quantitative RT–PCR were used to compare protein and mRNA expression of AR and 17HSD2 in endometrial biopsies from women with normal menstrual cycles and those using a LNG-IUS. RESULTS: Immunohistochemistry showed that AR and 17HSD2, which were immunolocalized to the stroma and glands of endometrium respectively, were both suppressed by LNG-IUS treatment, though moderate staining of 17HSD2 was evident 1 month after insertion of the LNG-IUS. AR mRNA expression was down-regulated in LNG-exposed endometrium when compared with the proliferative phase of the menstrual cycle. 17HSD2 mRNA was significantly increased 3 months (but not 6–12 months) after LNG-IUS insertion. CONCLUSIONS: Endometrial intracellular estradiol levels would have been suppressed by 17HSD2 during the first few, but not the later, months of LNG-IUS action, and the lowered endometrial estradiol level may contribute to the frequent BTB evident in the early months of LNG-IUS use. The subsequent decline in 17HSD2 would lead to elevated local intracellular estradiol in the later months, when the BTB tends to subside. The suppression of AR by the LNG-IUS may also play a role in BTB, as elevated AR has been associated with amenorrhoea.
Key words: androgen receptor/endometrium/17-hydroxysteroid dehydrogenase type 2/levonorgestrel
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