New findings from University of Vermont researchers Emma Wall, Ph.D., and Cory Teuscher, Ph.D., and colleagues provide insight into the gene pathways underlying responsiveness to estrogens and their potential role in the processes involved in such health concerns as fertility, postmenopausal bone loss, and sensitivity to environmental chemicals that disrupt the body’s endocrine system.

The study was published online January 31, 2013 in The FASEB Journal.

Estrogens are female sex hormones that are involved in a variety of physiological processes, including growth and development of the uterus and mammary gland. According to Wall, a postdoctoral associate in immunobiology, the response of reproductive tissues to the estrogen known as 17β-estradiol (E₂) is genetically regulated, but the mechanisms underlying the genetic control, and the pathways involved, are unknown.

In previous rodent model studies, Teuscher, a professor of medicine who has been studying the genetic control of uterine responsiveness to E₂ for 20 years, has identified several key genetic pathways underlying differential responsiveness to E₂. For this study, he, Wall and colleagues used two strains of inbred mice – one with high and one with low responses to E₂ – in order to examine E₂-regulated genetically controlled pathways. Their aim was to identify the genes and pathways associated with the differences in the uterine response to E₂ in each strain and, when comparing the strains at baseline, determine which of the genes and pathways that were expressed differently might regulate the uterotropic response. They also measured E₂-induced cellular changes that could be linked to the strain differences in tissue architecture after treatment with E₂.

Their findings revealed that the uterine response to E₂ is associated with at least 80 genes that are differentially expressed between the strains at baseline and are also located within the boundaries of previously identified regions of the genome influencing the uterotropic response to E₂.

“One of these genes, Runx1, has been recognized as being able to intensify E₂-signaling and might underlie the heightened uterine response to E₂ in the more sensitive mice,” says Wall. The research also showed that there are marked differences in E₂-induced uterine epithelial (surface) cell death, which Wall says could explain genetically-controlled differences in uterine weight.

Because the key factors involved in the regulation of uterine and mammary function are consistent across species, the team’s findings, though performed in mice, have direct application to other animals, including humans.

Elizabeth Bonney, M.D., UVM professor and director of research in obstetrics, gynecology and reproductive sciences, says “This is important work that provides a better understanding of the normal reproductive biology of women, and has implications for the treatment of infertility and evaluation of risk for endometrial cancer.”

“These results provide a potential explanation for differential responses to exposure to environmental estrogens noted in both mammalian and human studies and should enhance our understanding of potential vulnerable populations and help inform environmental health policy,” says Frances Carr, Ph.D., professor of pharmacology, whose research includes the study of the impact of environmental estrogens on thyroid cancer and development.

According to Teuscher, the current finding underscores comments by Jeffrey W. Pollard, Ph.D., director of the Center for Study of Reproductive Biology and Women’s Health at Albert Einstein College of Medicine, featured in an editorial review of his team’s article in Endocrinology (40:556-61, 1999): “A Holy Grail of the pharmaceutical industry is to find estrogens that are effective in one tissue but not others so that preventative treatments can be employed for bone loss, or in the prevention of cardiovascular disease, without increasing the risk of endometrial or breast cancer.”

The current findings delineating the gene pathways that affect estrogen responsiveness pave the way for the development of alternative therapeutic approaches.