Submitted to: Biology of Reproduction
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/29/2003
Publication Date: 1/7/2004
Citation: Kowalski, A.A., Vale-Cruz, D., Simmen, F.A., Simmen, R.C. 2004. Uterine androgen receptors: roles in estrogen-mediated gene expression and dna synthesis. Biology Of Reproduction. 70(1):1349-1357. Interpretive Summary: Androgens (also known as male hormones) are also present at high levels in the females, especial in the uterus. This study examined the proteins (called androgen receptors) within female cells that bind to androgens. The combination of the androgens and these proteins are responsible for many reactions within these cells. We found that the androgen receptor proteins are produced during early pregnancy in the pig and binding of androgens to their receptor proteins in the uterus can influence the expression of genes that are involved in further growth and differentiation of the uterus needed for a normal pregnancy (i.e., which are important for successful embryo development and implantation). Our center is extremely interested in how diet and dietary factors influence fetal and infant develop and the results found in the pig model may have important implications for successful fetal development.
Technical Abstract: The localization of androgen receptors (AR) and their ligands in the uterine microenvironment at early pregnancy suggest a role for AR in uterine physiology. We have evaluated AR expression in the pig uterine endometrium and examined whether AR ligands modulate peri-implantation uterine gene expression. Northern blot analysis demonstrated the ~10.5 Kb AR transcript in endometrium. Endometrial levels of AR mRNA and protein were greater at early- than at mid- or late-pregnancy. Estrogen receptor-' mRNA levels showed similar maximal expression at early pregnancy. Immunocytochemical analysis of endometrium at early pregnancy localized AR to nuclei of glandular epithelial (GE) and stromal (ST) cells. To evaluate a role for AR in uterine gene regulation, the levels of mRNAs for insulin-like growth factor-I (IGF-I), proliferative cell nuclear antigen (PCNA), and AR itself, were assessed in uterine endometrial explant cultures treated with 17ß-estradiol (E), testosterone (T), and 19-nortestosterone (N). Induction by E of AR mRNA abundance occurred in endometrium from day 10, but not from day 12 pregnant animals and this was partially blocked by co-addition of N or T, although neither androgen alone had any effect. Abundance of IGF-I and PCNA mRNAs was increased by E and inhibited by co-addition of either T or N in day 10 pregnant pig endometrium. In endometrium from day 12 pregnant animals, addition of either N or T with E increased IGF-I mRNA levels over that of controls, although E alone was without effect. In contrast, PCNA mRNA abundance was suppressed by all steroid treatments in these explants. DNA synthesis in primary cultures of GE cells from endometrium at days 10 and 12 of pregnancy was increased by E and was suppressed by T, the latter only at day 12. E did not affect DNA synthesis in ST cells from endometrium at either pregnancy day, although T inhibited this process in an E-dependent manner in ST cells from pregnancy day 12. Results identify AR in the pig endometrium during the window of maternal receptivity for implantation, and demonstrate the functional, albeit complex, interactions of androgens and estrogens in the regulation of uterine endometrial gene expression and cell growth in vitro. Further elucidation of the role of androgens and their receptor in early pregnancy events may be relevant to an understanding of peri-implantation embryo loss.