In Vivo Evidence of the Androgen Receptor in Association With Myometrial Cell Proliferation and Apoptosis

Abstract

Background:

The androgen receptor (AR) plays essential roles in female reproductive physiology. In vitro studies have shown that AR exerts 2 distinct but related functions in myometrial cells. The AR is required for myometrial cell cycling ligand independently, thereby controls myometrial cell proliferation. The AR also exerts antiapoptotic functions through myeloid cell leukemia 1 (MCL1) in both ligand-dependent and ligand-independent manners. However, these AR functions have not yet been confirmed in vivo. This study provides in vivo evidence that AR expression is associated with myometrial cell proliferation and apoptosis.

Methods:

Myometrial tissue was collected on day 6 of pregnancy from mice bearing an intact AR (AR+/+) or mice with AR heterozygous (AR−/+) or homozygous (AR−/−) functional knockout. Human uterine leiomyoma and paired myometrial tissue biopsies (n = 14 patients) were collected during hysterectomy. Immunohistochemistry was used to assess the protein expression of AR, MCL1, and Ki-67 index, as well as the functional associations of AR with MCL1 and Ki-67 index.

Results:

In AR−/− mice, MCL1 protein levels were reduced ∼50% in both circular and longitudinal myometrial cells when compared with that in AR+/+ and AR−/+ mice. By contrast, Ki-67 index remained unchanged. The AR protein expression and Ki-67 index in leiomyoma were ∼2- to 3-fold higher than that in normal myometrium. Although MCL1 expression was not coordinately increased in leiomyoma, strong positive correlations between AR and MCL1 expression were observed in leiomyoma but not in normal myometrium tissue.

Conclusion:

These results suggest that AR is an important regulator of myometrial growth in vivo during pregnancy and in leiomyoma.