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Infertility
With around 4 million babies born in the United States each year, conceiving a child can seem deceptively easy. This apparent fecundity obscures the fact that approximately 10 percent of people of reproductive age – or 6.1 million people in the United States – are infertile. The causes of infertility are varied, but about 40 percent involve a female factor.

In vitro fertilization-embryo transfer (IVF-ET) has aided many couples – but it is far from perfect. IVF-ET only has a 30 percent pregnancy success rate, even though the IVF process boasts a 60 percent to 80 percent fertilization rate.

“Many of these failures are likely due to implantation failure,” Dey says. “The uterus has to be receptive and the embryo has to be implantation competent…both have to be synchronized.”

Even in apparently fertile women, about three-fourths of all embryos fail to implant properly, leading to pregnancy loss before a woman even suspects she might be pregnant.

An incomplete understanding of the basic mechanisms of early pregnancy events has limited progress in treating infertility.

“Uterine biology and embryo-uterine interactions are so unique and involve so many cells that we don’t really understand the process of implantation in depth,” says Dey, the Dorothy Overall Wells Professor of Pediatrics, professor of Cell & Developmental Biology and Pharmacology, and director of the division.

Hormones from the ovary – estrogen and progesterone – signal to the normally inhospitable uterus to prepare it to receive the developing embryo (at this point, called a blastocyst). If, at the end of its journey down the fallopian tubes, the blastocyst finds the lining of the uterus properly prepared, it attaches, secretes enzymes and undergoes cellular changes to help it burrow into the uterine wall where it continues its growth.

This “window of implantation” – when the uterus is receptive and the blastocyst is competent – is brief. And timing is critical.

“Implantation is the gateway to a successful pregnancy. If you tinker with the window of implantation – even by a few hours – it creates an adverse ripple effect throughout pregnancy…and pregnancy outcome is very poor,” says Dey, the first Vanderbilt investigator to hold two simultaneous MERIT (Method to Extend Research in Time) awards from the NIH.

Dey and colleagues have demonstrated the outcome of this deferred implantation “ripple effect,” which can manifest itself in mice by reduction in size of the litter. For example, a normal litter size is eight to nine pups. If implantation is deferred, the mother may give birth to only two to four pups, and they are usually smaller.

In 2003, Dey showed that the window of uterine receptivity depended on a very tight range of estrogen levels. By giving ovariectomized pregnant mice daily doses of progesterone, the researchers kept the developing embryos in a state of “delayed implantation,” where the embryos lay dormant for several days, awaiting the proper signals for implantation. They then tested varying levels of estrogen, finding that a single injection of just 3 nanograms of estrogen kept the uterus receptive for up to four days. Higher doses shrunk the receptive window considerably, sometimes blocking implantation.

The study showed that high levels of estrogen alter the expression of implantation-related genes in the uterus, abolishing uterine receptivity to the embryo. Using genetically engineered mice, Dey is hopeful that he will be able to find ways to extend the receptive phase.

Although it is not clear if delayed implantation occurs in humans, it is clear that estrogen also plays a key role in implantation in humans. Estrogen levels can reach very high levels following some fertility treatments and from exposure to environmental chemicals that mimic estrogen (xenoestrogens) and dietary plant estrogens (phytoestrogens), posing a possible threat to implantation or alteration of the window of implantation.

Dey’s group found out the hard way that phytoestrogens influence the implantation process when his group moved to Vanderbilt in 2002. Many of the studies he had been conducting for nearly 30 years at his former post at the University of Kansas Medical Center were not working in his new location.

“This was a nightmare coming to Vanderbilt,” he recalls. Even though they were using the same strain of mice from the same source, they couldn’t replicate several experiments that they had performed in Kansas – a major worry in continuing their research.

“Many factors could be responsible for these observed differences between the two sites – animal bedding, water, viral load in the environment and mouse chow. Among many factors, we chose to focus on mouse chow. The mouse chow used here has higher plant estrogen levels (than that used in Kansas),” says Dey. “So, the staff veterinarian arranged for two types of diet – with low phytoestrogen and high phytoestrogen – and we found out the difference.”

They found that the diet with high levels of phytoestrogens altered uterine responses to estrogen and the expression of genes regulated by estrogen. The diet also shifted the implantation window ahead approximately four hours.

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