Proliferative Action of the Androgen Receptor in Human Uterine Myometrial Cells—A Key Regulator for Myometrium Phenotype Programming

• Published in: The journal of clinical endocrinology and metabolism 2013-01, Vol.98 (1), p.218-227
• Main Authors: Liu, Liangliang, Li, Yunqing, Xie, Ning, Shynlova, Oksana, Challis, John R. G, Slater, Donna, Lye, Stephen, Dong, Xuesen
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Cell Proliferation; Cells, Cultured; Embryonic Development - genetics; Embryonic Development - physiology; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gestational Age; Humans; Medical sciences; Metribolone - pharmacology; Myometrium - cytology; Myometrium - metabolism; Myometrium - physiology; Phenotype; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Pregnancy - genetics; Pregnancy - metabolism; Rats; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Receptors, Androgen - physiology; Testosterone Congeners - pharmacology; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2012-2451

Context: During pregnancy, the myometrium undergoes a phenotype programming starting from an early proliferative stage, to an intermediate synthetic stage, to a late contractile stage, after which the cells commit to labor. Steroid receptors play important roles in regulating myometrial cell phenotype during pregnancy, although detailed mechanisms are not fully defined. Objective: The aim of the study was to investigate the expression and function of the androgen receptor (AR) in myometrial cells during pregnancy. Design and Setting: Human primary myometrial cells, immortalized myometrial cells, rat pregnant and tubal ligation models were used. Immunohistochemistry, Western blot and real-time PCR, cell proliferation, and flow cytometry assays were applied. Results: The AR is highly expressed in the proliferative stage of pregnancy, starts to decrease in the synthetic stage, and reaches the lowest levels in the contractile stage. Both the mechanical stretch by the growing fetus and the decreased ratio of progestin:estrogen are responsible for AR protein reduction. AR regulates myometrial cell proliferation ligand-independently. Decreased AR expression delays the G1-S phase transition of human myometrial cell cycling and reduces expression of several cyclins. These AR actions are mediated through reducing IGF-I receptor protein stability, thus weakening PI3K/Akt signal cascade downstream of IGF-I. AR is required for IGF-I receptor protein stability by preventing the IGF-I receptor from ubiquitylation and protein degradation through both proteosomal and lysosomal pathways. Conclusion: AR is a key regulator for myometrial cell proliferation, suggesting its critical role in myometrium phenotype programming during pregnancy.