Estrogens- estrone (E1), estradiol (E2), estriol (E3)- are synthesized predominantly in the ovary and are steroid hormones essential for the development of female sex characteristics and reproduction. During pregnancy, E3 levels increase abruptly. Until now, scientists had no idea what this hormone does or why levels of it build as they do.
But now, thanks to a discovery by Yale University, scientists found the role of this mysterious Estrogen. For the first time, they discovered that estriol plays a vital role in shaping offspring’s future.
Hugh S. Taylor, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, Yale University, said, “Humans and some other primates evolved a complex pathway of estriol production that’s not seen in most animals. It was made specifically in pregnancy for a particular function that nobody knew about until now.”
To better understand the role of E3, scientists treated pregnant mice- which don’t naturally produce the hormone- with estriol. They then observed how its administration impacted the offspring’s brain and uterus.
The administration of E3 has been shown to improve pregnancy rate, litter size, the success of pregnancy, and uterus structure. Offspring also showed less anxiety and greater exploratory behavior.
The scientists then looked for changes in gene expression when baby mice became adults to explain the improvements. As a result of the procedure, that generation’s offspring revealed many genes that were differentially expressed.
Taylor said, “These mice were exposed as a fetus when their mom was pregnant. We saw permanent changes in gene expression that remained long after the exposure was done.”
The mechanism by which estriol causes epigenetic alteration was also discovered in the study. Unlike estradiol, the binding of estriol to estrogen receptors on proteins changes the structure of estriol, allowing it to bind to epigenetic modifiers. This modifies its binding to target genes. It is paradoxically a very strong estrogen when one looks at this novel estrogen action.
Taylor said, “Estriol programs reproductive potential and brain function through epigenetic modification. It does this by allowing the estrogen receptor to bind with new binding partners that are epigenetic modifiers.”
The finding raises the fascinating possibility that if doing so is found to be safe, adding estriol during human pregnancies might become a way to make those pregnancies safer and less prone to complications.
In future studies, the team seeks to understand better how other estrogens cause epigenetic programming and how to prevent dangerous exposures, especially in pregnant women. They are also interested in learning more about the genes regulated by estriol to gain a better understanding of the pathway.
Taylor said, “Now that we understand this function and mechanism, we’re trying to define what environmental agents interfere with human development and lead to problems later in life.”
- Zhou, Y., Gu, B., Brichant, G. et al. The steroid hormone estriol (E3) regulates epigenetic programming of the fetal mouse brain and reproductive tract. BMC Biol 20, 93 (2022). DOI: 10.1186/s12915-022-01293-4