Thanks to recent research conducted by scientists at the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU), a new avenue to in vitro fertilization (IVF) could soon be opened for prospective parents who were previously told it was unadvisable or impossible.

A perfect embryo contains 46 perfect chromosomes, but some have more, and others have fewer. The result is a common abnormality known as aneuploidy, which occurs in as many as 80 percent of human embryos. Because aneuploidy has been linked to a risk of in vitro fertilization failure, miscarriage and certain genetic orders or birth defects, mosaic embryos— those with both normal and abnormal cells—have not been considered ideal candidates for IVF transfer.

For prospective mothers who only produce mosaic embryos, this can mean the IVF journey may end before it begins. But that could change very soon.

The ONPRC study, led by Shawn L. Chavez, PhD, an assistant professor of reproductive and developmental sciences at ONPRC at OHSU, and an assistant professor of obstetrics and gynecology, and physiology and pharmacology in the OHSU School of Medicine, is the first to confirm mosaic embryos can adapt and persist in development in a nonhuman primate model, resulting in positive IVF outcomes.

Using advanced time-lapse imaging and single-cell sequencing techniques to precisely track the development of mosaic embryos of a rhesus macaque, Chavez and team identified a relationship between mosaicism and two other biological processes: cell fragmentation and blastomere exclusion.

In utero and after IVF, large cells formed by the division of a fertilized egg, known as blastomeres, may break down into small pieces called cellular fragments. These fragments, it seems, can serve as a sort of cellular cleanup crew.

“We found that both the blastomeres and their fragments can act as trash bins within the embryo. As DNA-carrying cells divide and/or fragment, the embryo appears to naturally identify which blastomeres have genetic abnormalities and stop them from further development,” said Chavez.

He further explained that by the stage in which an embryo would implant into the uterus, these abnormal cells or DNA have been visibly excluded from the rest of the embryo, suggesting that imperfect IVF embryos could be considered for use in transfer and could possibly endure in utero.

According to Paula Amato, MD, an associate professor of obstetrics and gynecology in the OHSU School of Medicine, this discovery could positively impact IVF processes for humans in the future.

 “While selecting embryos with a normal chromosome complement is preferred and carries a high chance of pregnancy success, it is not a guarantee,” she explained. “For patients with only mosaic embryos available for transfer, these findings suggest that in some cases, these embryos will result in apparently normal pregnancies.”

Ongoing research will use live-cell time-lapse imaging to better understand the relationship between aneuploidy, cell fragmentation and blastomere exclusion within the embryo. The scientists believe these results could open up new avenues for testing mosaic human embryos.

“We expect that the overall results will be similar to the story of the ‘dark horse,’” said Chavez. “While not perceived as a contender at the start of the IVF race, a mosaic embryo may still be capable of winning and resulting in something wonderful.”

Medications like chemotherapy and radiation are highly effective in treating cancer and benign tumors, but these therapies can also increase the risk of infertility. One in three childhood cancer survivors carry this risk, and for those undergoing treatment prior to puberty, common fertility preservation processes for adults—such as sperm or egg freezing—are not an option. 

But there may be newfound hope.

Recent research from the University of Pittsburgh School of Medicine, Magee-Women’s Research Institute and Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University has found immature testicular tissue can be cryopreserved, or frozen, and later used to restore fertility.

Using a nonhuman primate model of cancer survivorship, the researchers removed one testis each from prepubertal rhesus macaques and cryopreserved the immature testicular tissue. Later, the researchers thawed and transplanted pieces of the tissue under the skin of the same animal.

Approximately one year later, the testicular skin grafts were removed and compared to samples of the immature tissues. Not only were the grafts able to produce enough testosterone for the animal to undergo puberty, but they were also found to contain an abundance of mature sperm.

Scientists at ONPRC then used the samples to generate viable embryos through intracytoplasmic sperm injection, or ICSI, where individual sperm were recovered from the graft tissues and injected directly into an egg. The embryos were successfully transferred to recipient females, and in April 2018, a healthy female baby named “Grady” was born.

“The ability and choice to have a family should not be determined by the risks of necessary medical treatment,” said Carrie Hanna, PhD, director of the Assisted Reproductive Technology Core at ONPRC. “Grady represents an important step toward ensuring that children maintain their opportunity to have a family later in life, should they choose to do so.”

When preparing for motherhood, no mom-to-be should have to worry about a potentially life-threatening illness. And thanks to the work of researchers at Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW), we’re one step closer to controlling a disease which exclusively affects pregnant women.

Preeclampsia raises a mother’s blood pressure, threatening both her life and her baby’s. Symptoms usually include water retention and protein in the urine, as well as rarer and more severe effects like liver or kidney failure.

The disease is treatable if detected early and handled with regular prenatal care, but no one knows its cause or how to prevent it. However, two studies by WiNPRC researchers have offered promising insights.

In one study, researchers discovered testosterone levels in preeclamptic women are elevated two to three times above normal levels. Animal models of preeclampsia also showed patterns and levels of increases in testosterone mimicking those found in women. This correlated positively with vascular dysfunction and higher placental androgen (hormone) receptor gene expression.

In a closely related study, scientists using an animal model found maternal vascular adaptation to pregnancy is critical for blood flow through the placenta to the developing baby. If vasculature can’t properly adapt, the mother may develop preeclampsia and other hypertensive disorders.

These discoveries could help scientists create life-saving treatments.

“With these confirmed animal models of preeclampsia, we can now dig deeper to uncover the etiology and pathogenesis of preeclampsia to gain a better understanding of the disorder and advance treatments and preventions for women,” explained David Abbott, Ph.D., of WiNPRC.

Elevated risk for diabetes and weight gain is a well-documented issue for post-menopausal women—but its biological cause isn’t as certain.

Contradicting past studies, researchers at the Wisconsin National Primate Research Center (WiNPRC) have learned that a naturally-occurring decline in one specific hormone may not be a significant factor in post-menopausal health risks, as previously thought. An article published July 19 in the International Journal of Obesity shows a much smaller role for ovarian estradiol—a steroid hormone—in female metabolism than previously thought.

In prior studies with adult female rodents, ovarian estradiol has been shown to regulate body weight, energy balance and other factors while also protecting against diet-induced obesity.

“We thought these actions also occurred in primates, but our research indicates otherwise,” said Marissa Kraynak, PhD, who co-authored the study with Ricki Colman, PhD.

To test the metabolic functions of ovarian estradiol in female nonhuman primates and discover what happens when the hormone is removed, scientists at WiNPRC selected the common marmoset monkey, which is modestly susceptible to diet-induced obesity. They studied the effects of estradiol depletion combined with diets higher in fat and sucrose, hypothesizing that this would increase body weight and decrease glucose tolerance.

“But we were surprised to see no changes in feeding behavior, activity or energy expenditure in our study monkeys,” Kraynak noted.

The study results suggest that ovarian estradiol may not be a major contributor to metabolic health in female primates. This also leaves open the intriguing possibility that estrogens produced elsewhere in the body—including the brain—may function in this capacity in both nonhuman primates and women.

‘Hippies’ are not all human; nonhuman primates have their own flower children. The muriqui monkey boasts famously low rates of aggression, spending much of its time hugging and socializing, and displays no hierarchy among males and females. Yet, through the work of a Brazilian-American research group led by Karen Strier, professor of Anthropology at the University of Wisconsin-Madison, the muriquis have emerged as a charismatic animal in need of help as habitat delines and populations dwindle.

In the effort to preserve the 2,300 muriquis in the wild, the research group asked an all-important question – What data do we need?

This question is especially important for studying multiple populations with differing habitat requirements, like northern and southern muriquis. Previous studies failed to maintain consistent methods, which produced results that were not comparable, so this team’s efforts are groundbreaking. “We think this may be one of the most comprehensive efforts to analyze the data monitoring needs for ensuring the survival of an endangered animal,” says Strier.

The study identifies genetic uniqueness and geographic importance as two key measurements that indicate whether a population can be used to enhance genetic diversity. Sex ratio and the proportion of females carrying babies allow scientists to understand population change. Methods should address feasibility, since many species inhabit locations impossible to reach, and be wary of fringe sites, as outlier populations are especially sensitive to climate changes.

Scientists are already applying this methodology to the northern and southern muriqui populations. The team is hopeful these methods can be used to study and save other endangered species.

The peaceful primates’ luck is looking up, as new muriqui reserves and abandoned farms make for hospitable environments to call home. “Seeing the resilience of nature makes me more determined than ever,” explains Strier. “We can’t reverse the past assaults to the planet, but we can do everything we can to stop them and give the animals and plants a chance to come back.”

Reviewed August 2019

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Photo credit: Wisconsin National Primate Research Center

What causes infertility? The brain, of course.

With the discovery in 2013 that the ovaries weren’t the only producer of estrogen, researchers at the Wisconsin National Primate Research Center (WiNPRC) wanted to know how estradiol, the type produced by the hypothalamus region of the brain, affected the estrogen feedback loop.

This hormonal mechanism is the back and forth communication between the brain, pituitary gland and ovaries that regulates the menstrual cycle. The brain and pituitary gland tell the ovaries to produce estrogen. Estrogen then tells the brain and pituitary gland to release hormones. Those hormones then tell the ovary to release an egg. But after the discovery that the brain also produced estrogen, scientists at the Wisconsin National Primate Research Center wanted to know how these two sources of estrogen interact.

Using rhesus macaques as test subjects, they temporarily stopped their ovaries from producing estrogen. They also implanted a capsule under the monkeys’ skin that would release estradiol. The result? The brain and pituitary gland released only 30 percent of the luteinizing hormone necessary to begin ovulation.

Then, the researchers repeated the process, but this time, they blocked estradiol production in the hypothalamus. But without the estrogen produced by the brain, the hormones weren’t concentrated enough to release an egg.

“The ovarian estrogen starts the [hormone] surge, but the brain estrogen allows the surge to continue,” says Brian Kenealy, a researcher at the WiNPRC.

“This shows the brain’s estrogen is a huge helper, necessary for the release of an egg that makes pregnancy possible,” says Ei Terasawa, a pediatrics professor at the UW-Madison School of Medicine and Public Health and senior scientist at the Wisconsin National Primate Research Center. “We have to modify our concept of the feedback loop.”

For women struggling with infertility, this finding may unlock future treatments. For now, it’s a step forward in our understanding of the estrogen feedback loop.

Reviewed August 2019

In the United States, 64 percent of women of reproductive age are overweight and 35 percent are obese. New research at the Oregon National Primate Research Center (ONPRC) links an unhealthy diet during pregnancy to mental health disorders, such as anxiety and depression, in children.

The study, led by Dr. Elinor Sullivan, an assistant professor in the Division of Neuroscience at ONPRC at OHSU in Portland, Oregon, tested the effect of a maternal high-fat diet on nonhuman primates, tightly controlling their diet in a way that would be impossible in a human population. The study revealed behavioral changes in the offspring associated with impaired development of the central serotonin system in the brain. Further, it showed that introducing a healthy diet to the offspring at an early age failed to reverse the effect.

Previous observational studies in people had correlated maternal obesity with a range of mental health and neurodevelopmental disorders in children. The new research demonstrates for the first time that a high-fat diet, increasingly common in the developed world, caused long-lasting mental health issues for the offspring of nonhuman primates. “It’s not about blaming the mother,” said Dr. Sullivan.

“It’s about educating pregnant women about the potential risks of a high-fat diet in pregnancy and empowering them and their families to make healthy choices by providing support. We also need to craft public policies that promote healthy lifestyles and diets.”

Researchers assigned a total of 65 female Japanese macaques into two groups, one given a high-fat diet and one a control diet during pregnancy. Then they measured and compared anxiety behavior among 135 offspring and found that both males and females exposed to a high-fat diet during pregnancy exhibited greater incidence of anxiety compared with those in the control group. The scientists also examined physiological differences between the two groups, and found that exposure to a high-fat diet in early development impaired the development of neurons containing serotonin, a neurotransmitter that’s critical in developing brains.

Sullivan believes the findings provide evidence that mobilizing public resources to provide healthy food and pre- and post-natal care to families of all socioeconomic classes could reduce mental health disorders in future generations.

The World Health Organization estimates that about 225 million women in developing countries would like to delay or stop childbearing but are not using any method of contraception.

Dr. Jeffrey Jensen of the Oregon National Primate Research Center is working to develop a low-cost, safe and highly effective method of nonsurgical permanent contraception that will meet the needs of women in low-resource regions, but also be of interest to women in resource-rich countries.

“When women have completed their family size, or wish to not have children, many prefer a noninvasive, effective and permanent form of birth control,” said Jensen. “Particularly in low-resource settings where there is no choice but to continue bearing children, women benefit greatly from a safer form of permanent contraception.”

“Many of the patients I see have had good success with reversible contraception methods, but still desire a permanent method,” he continued. The only permanent form of contraception currently available to women is tubal ligation, which “requires, at a minimum, one counseling visit, one pre-operative visit, and one half-day in the day surgical unit or procedure room. The inconvenience and time burden for my patients provides a strong motivation for me to come up with a better approach.”

Dr. Jensen believes that the approach to permanent contraception should be the same for women in lesser developed as in more developed nations. To be acceptable in regions with low resources, like sub-Saharan Africa, women and health care providers need to know that a method is safe and well-accepted by well-to-do women in resource-rich nations, he says.

With a grant from the Bill & Melinda Gates Foundation, Jensen launched the Oregon Permanent Contraception Research Center at the Oregon National Primate Research Center.

Jensen’s team uses nonhuman primates to study nonsurgical approaches to permanent contraception for women, because of the unique anatomic features and reproductive physiology they share with women. Using the baboon model, Jensen’s research has demonstrated that transcervical administration (similar to the placement of an IUD) of a single dose of polidocanol foam can result in a high rate of tubal occlusion and prevent pregnancy. The addition of doxycycline may improve efficacy, and refinements of the approach to demonstrate safety are in progress as the team hopes to transition the research into early phase clinical trials in women.

Updated August 2019