Estrogens are the major contributor to uterine development but androgens, acting via the androgen receptor (AR), can also promote uterine growth. We demonstrated that global AR inactivation in mice (ARKO) reduces uterine growth  and now test the hypothesize that androgens acting via AR can fully support uterine growth with the growth promoting effect of androgens mediated via AR in uterine endometrial glands.
To test our hypothesis, we used global ARKO and glandular epithelial ARKO (utARKO) mouse models to investigate uterine development (20 weeks) compared with wild-type (WT) females. Additionally, these mice were ovariectomised and treated with testosterone (OVX+T), DHT (OVX+DHT) or empty implant (OVX+empty).
Uterine weights in intact [~96±9mg (mean±SE)] and OVX+empty (~12±2mg) groups were not affected by genotype. Uterine growth following OVX+T was modified by AR inactivation. No regrowth was observed in ARKO [14±1mg], while the uterine weight in utARKO [57±3mg; n≥8] was significantly (p<0.05) increased compared to ARKO but significantly reduced compared to WT [95±10mg] that had full uterine regrowth. Histomorphologically, both the endometrial and myometrial areas were significantly (p<0.05) reduced in utARKO (0.4±0.1 and 0.7±0.1mm2 respectively; n≥5) compared to WT (0.7±0.1 and 1.5±0.5mm2; n≥5), suggesting that inactivation of glandular epithelial AR modified uterine growth. ARKO uteri were undeveloped demonstrating that the uterine regrowth following T replacement is AR mediated.
Furthermore, WT(OVX+DHT) mice (86±16mg; n≥3) achieved similar uterine weights as WT(OVX+T) suggesting that androgens alone can promote full uterine regrowth and does not require estradiol.
In conclusion, androgens acting solely via AR can support full uterine growth. Furthermore, glandular epithelial AR mediates uterine (including myometrial) growth via AR mediated androgen actions. Thus further investigation of the role of AR and cross-talk involving AR expression in different type of cells is warranted. This could lead to better biomarkers and more effective novel treatment of uterine disorders.