Local levonorgestrel regulation of androgen receptor and 17beta-hydroxysteroid dehydrogenase type 2 expression in human endometrium.
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 17beta-hydroxysteroid dehydrogenase type 2 (17betaHSD2) regulates intracellular levels of estrogens, progestins and androgens, we evaluated the changes in expression of 17betaHSD2 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 17betaHSD2 in endometrial biopsies from women with normal menstrual cycles and those using a LNG-IUS.


RESULTS
Immunohistochemistry showed that AR and 17betaHSD2, which were immunolocalized to the stroma and glands of endometrium respectively, were both suppressed by LNG-IUS treatment, though moderate staining of 17betaHSD2 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. 17betaHSD2 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 17betaHSD2 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 17betaHSD2 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.
Burton
Kevin A
KA
Centre for Reproductive Biology, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
Henderson
Teresa A
TA
Hillier
Stephen G
SG
Mason
J Ian
JI
Habib
Fouad
F
Brenner
Robert M
RM
Critchley
Hilary O D
HO
D015067:17-Hydroxysteroid Dehydrogenases / Q000032:analysis / Q000235:genetics*; D001706:Biopsy; D003271:Contraceptive Agents, Female / Q000008:administration & dosage* / Q000009:adverse effects; D004717:Endometrium / Q000737:chemistry*; D004958:Estradiol / Q000032:analysis; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007436:Intrauterine Devices, Medicated / Q000009:adverse effects; D016912:Levonorgestrel / Q000008:administration & dosage* / Q000009:adverse effects; D008597:Menstrual Cycle; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014592:Uterine Hemorrhage / Q000139:chemically induced
D003271:Contraceptive Agents, Female; D012333:RNA, Messenger; D011944:Receptors, Androgen; D004958:Estradiol; D016912:Levonorgestrel; D015067:17-Hydroxysteroid Dehydrogenases