Endocrine Abstracts (2015) 38 P386 | DOI: 10.1530/endoabs.38.P386

Impact of 5[alpha]-dihydrotestosterone (DHT) on glandular epithelial proliferation in the mouse uterus

Ioannis Simitsidellis1, Fiona L Cousins1, Douglas A Gibson1, Lee B Smith2 & Philippa T K Saunders1

1The Queen’s Medical Research Institute, Centre for Inflammation Research, Edinburgh, UK; 2The Queen’s Medical Research Institute, Centre for Reproductive Health, Edinburgh, UK.

The uterus is an androgen-responsive organ; androgen receptors (AR) are expressed in human endometrial stromal fibroblasts and can regulate proliferation and survival of this cell type. Although chronic androgen exposure results in atrophy of human endometrium, previous studies have suggested that it may have trophic effects in the rodent uterus. We hypothesised that androgens may have different impacts on endometrial function in the presence or absence of oestrogens. In the current study we investigated the effects of the non-aromatisable androgen DHT (alone and in combination with 17β-oestradiol, E2) using both short-term (24 h) and long-term (7 days) dosing regimes. Eight-week old C57BL/6 female mice were ovariectomised; 7 days later they were given a s.c. SILASTIC implant (empty control or E2). After a further 7 days (day 14) they received either 1× or 7× daily s.c. DHT (0.2 mg/mouse). Mice were culled 24 h after the last DHT injection; 2 h prior to death they received a single intraperitoneal injection of BrdU. Uteri were collected and processed for immunohistochemistry and gene expression analysis (qRT-PCR). Treatment with E2 alone induced an increase in uterine weight and endometrial surface area; treatment with DHT alone induced a similar effect after 7 days of treatment. Treatment with DHT alone altered gene expression in glandular epithelial cells so that they became AR+ which was accompanied by increased cell proliferation (cyclinD1+/BrdU+/MKi67+). Gene expression analysis identified significant changes in mRNA concentrations of Igf1, MKi67, Wee1 and Rb1 with E2 either blunting or masking the DHT response.

In conclusion, in mice the impact of androgens on endometrial tissue is dependent upon whether oestrogens are present. It is notable that metestrus is characterised by low oestrogens/androgens ratio. We speculate that androgens may also be important in regulating endometrial tissue remodelling when oestrogens are low at the time of menses.

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