Innovative research on cattle herds improves understanding of female infertility

Innovative research on cattle herds improves understanding of female infertility

Innovative research by University of Nebraska-Lincoln scientists studying the reproductive biology of cows offers significant long-term potential to address the challenges of infertility in women.

Reproductive physiologist Andrea Cupp and her colleagues in the Department of Animal Science are furthering understanding of bovine reproductive biology using advanced genetic analyses, reproductive tissue culture and other tools.

This basic research may have significant applicability in understanding the challenges of human infertility, due to the many general parallels in the reproductive biology of cows and women, said Cupp, Professor of Animal Science Irvin T. and Wanda R. Omtvedt.

“Cows ovulate one egg each reproductive cycle,” Cupp said. “The gestation period – the incubation time of a fetus – is similar: nine months. Cows have a similar reproductive cycle, similar endocrine hormones and similar ovary size. This is directly applicable to women’s human conditions.

Cattle face significant infertility issues, Cupp said. An example is anovulation, the failure to release or irregular release of an egg from the ovary during the reproductive cycle.

“Cows have a lot of anovulation issues, like many other species, including humans,” said Cupp, who earned her master’s and doctorate degrees in Nebraska.

Cupp and his colleagues found an additional parallel: a significant percentage of cows studied by Husker scientists show symptoms similar to those experienced by women with polycystic ovary syndrome (PCOS), one of the most common infertility conditions in the United States. PCOS affects between 6% and 11% of American women of childbearing age.

Irregular reproductive cycles are one of the three main symptoms associated with PCOS. A second factor is an excess of androgen hormones. The third factor: the follicles in the ovary, each containing an immature egg, fail to develop, in a condition called “follicular arrest”.

Cupp found that the herd in his study was notable for the surprisingly high levels of androgens in many cows, similar to the condition of females with PCOS. She also found that a significant percentage of heifers reached puberty prematurely, while a notable percentage developed quite late. These are also common conditions for many women with PCOS.

The results marked cows as a good model for research into female infertility. Her Husker colleagues, Cupp said, are major contributors to the scope of this study.

Jennifer Wood, professor of reproductive molecular and cellular biology, studied PCOS as a postdoctoral fellow and was a major collaborator on the project. Bob Cushman, physiology researcher at WE The Meat Animal Research Center in Clay Center, Nebraska has been helpful in developing techniques to obtain ovarian tissue for study. To help understand the genetic impact, several scientists contributed: Jessica Peterson, associate professor in animal functional genomics; Matt Spangler, Professor and Specialist in Bovine Genetics; and Melanie Hess, quantitative geneticist and assistant research professor.

Recently, Ligia Prezotto, neuroendocrinologist and assistant research professor, joined the team to study how a mother’s exposure to increased hormones during pregnancy can wire the fetal brain differently and contribute to PCOS-similar symptoms.

Scientific research on women’s health, including fertility, has long faced major obstacles because the study of disorders and many biological systems has traditionally used male animal models instead of female models.

It is more difficult to study female physiological processes because of the complications created by the female reproductive cycle. Yet these hormonal differences during the menstrual cycle in women and the reproductive cycle in female cattle are critical to their health and response to disease, warranting detailed scientific understanding.

Women “are very little studied as a gender, whether in humans or animal models” when it comes to research, Cupp said.

Cupp’s research focuses in particular on factors that can restore the proper formation of blood vessels in the ovaries, which can promote the healthy development of the ovarian follicles that contain the egg. A key target is vascular endothelial growth factor, a protein that guides cellular signals for a variety of important blood vessel actions.

His graduate students used growth factor to treat pieces of bovine ovaries, to see if the protein can promote healthy follicle development. With this innovative lab approach, “we basically saved those follicles and those bits of ovary from our androgen-rich cows,” she said.

“We genotype the herd,” Cupp said, “and sequence their DNA to see if we can figure out what contributes to genetic variation in the herd, and hopefully link that to their pubertal or reproductive characteristics.

Cupp highlighted the significant mentorship and support she received from John Davis, professor and director of the Nebraska Center for Women’s Health Research at the University of Nebraska Medical Center.

PCOS has long been difficult to understand medically because it is affected by a wide range of factors, including genetics and environment. Ultimately, Cupp said, researchers will need to look at the results in a way that is understandable for the breadth of populations studied, both animal and human.

A key thing, she said, is that researchers avoid rigid assumptions.

“As scientists, we have to observe things, we have to keep an open mind,” she said. “We have to follow what the data tells us.”

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