UW Researchers Study Genetic Disruptions That Lead to Infertility, Disease

University of Wyoming scientists will use a $1.65 million National Institutes of Health grant to continue research into understanding endocrine signaling mechanisms between the ovary and uterus that contribute to infertility and diseases when disrupted.

The cost of faulty endocrine (hormone) signaling between the ovary and uterus to humans and agriculturally important domestic species is tens of billions of dollars a year, says Jim Pru, a professor and the Rochelle Chair in the UW College of Agriculture and Natural Resources.

Pru’s laboratory was the first to evaluate the expression and function of a family of genes called the progesterone receptor membrane component (PGRMC) family, which mediate some of the actions of the female sex steroids estrogen and progesterone in the female reproductive system.

“These sex steroids, when produced at various stages of either the estrous or menstrual cycle, will coordinate molecular events in the uterus in preparation for embryo implantation, but binding to and activating specific proteins,” says Pru, who joined the UW Department of Animal Science in January. “The endocrine signaling that exists between the ovary and uterus is a sophisticated way for two organs to communicate with one another to ensure the uterus is properly primed for early pregnancy.”

He says the signaling between the ovary and uterus occurs in all mammals -- no matter if humans, cows, pigs, horses, domestic animals or rodents.

“These are evolutionarily conserved pathways and have applications to not only large domestic animal species, but also to human reproductive functions,” says Pru, a Wyoming native and UW graduate.

Before returning to UW, Pru had a split appointment between the Agricultural Research Center and academic programs at Washington State University (WSU) in Pullman, Wash. He also served as associate director at WSU’s Center for Reproductive Biology.

Pru’s lab uses conditional mutagenesis as a way to understand if, and how, certain genes function in the uterus during early pregnancy and in the development of women’s reproductive diseases.

“That’s the approach my laboratory uses,” he says. “We knock genes in or out of just the uterus, and then we evaluate the function of these genes based on the outcome. An understanding of gene function gives us the ability to understand the basic biology of reproductive physiology at the molecular level, and to then work toward developing therapeutic strategies to combat infertility and diseases for the female reproductive system. So, the question is: How do female sex steroids function to coordinate events in the uterus of early pregnancy?”

Scientists evaluate gene mutations and use breeding trials to understand what’s occurring in the absence or overexpression of those genes.

“The importance of these studies is that we’ve got all sorts of reproductive issues in domestic livestock,” Pru says. “Beef cattle have issues. Dairy cattle have issues in generating offspring. Many of these reproductive issues occur during the early stages of pregnancy when the embryo signals its presence to the mother as the embryo implants into the uterine wall. These reproductive issues contribute to billions of dollars of losses to livestock producers. So, it is not insignificant. We also know there are tremendous infertility issues in humans.”

For example, when the uterus does not respond properly to the female sex steroids estrogen and progesterone, this contributes to pregnancy loss and development of reproductive diseases. “And they are huge, huge issues,” he says.

Endometriosis is one of the human diseases when the process derails.

“Endometriosis is really a big one, and a little bit near and dear to my heart because we do study that in the lab,” Pru says.

Affecting one in 10 women, the disease causes the menstrual flow, instead of going outside the body, to flow in retrograde fashion through the fallopian tubes into the peritoneal cavity, causing benign, highly inflammatory lesions that become infiltrated with blood vessels.

“The main issue is pain, of course, but it also causes infertility,” he says. “And most women who are diagnosed with endometriosis don’t even know they have it.”

Laparoscopic surgery is the only way to diagnose the disease.

“There is no long-term cure for the disease aside from menopause or removing the ovaries, because this disease, as with most hyperproliferative diseases of the female reproductive system, is driven by estrogen that comes from the ovary,” Pru says. “They manage the disease to prevent it from becoming highly inflammatory and causing pain and infertility, but there is really no cure for this disease.”

Interestingly, he says, members of the PGRMC family are known to be misregulated in patients with endometriosis.

It’s also a $22 billion burden in the United States, from lost wages due to not working because of pain and to treating the condition, as well as medical costs.

“The staggering statistic to me -- forget the economics -- is the fact it’s so prevalent, and that there’s no cure and no real good diagnostic for this particular disease,” Pru says.

Pru’s lab has established that PGRMC protein expression is elevated in different types of cancer.

“We’ve done work in our own lab, and we know that PGRMC1, for example, is elevated in endometrial, ovarian and breast cancers,” he says. “It’s expressed about four times the normal levels in endometrial cancer.”

The lab’s studies are important not only for fertility issues, but they’re also important because these proteins are misregulated in disease conditions, he says.

The genes are evolutionarily conserved and, “if you have the protein or the gene expressed and it plays an important role in cows, in mice, humans and nonhuman primates, then it’s probably a pretty important protein or gene,” Pru says.