Cattle herding research improves understanding of female infertility

Andrea Cupp (right) shows Ailenn Castillo, a senior forensic scientist major, how to obtain plasma from blood samples from research cows. Cupp demonstrates the centrifuge process for separating the blood components so that the DNA can be stored and the cows can be genotyped. Eric Buck/Zoiology | courtesy photo

Lincoln, Nebraska, December 8, 2022 – Innovative research by University of Nebraska-Lincoln scientists studying the reproductive biology of cows offers significant long-term potential to address the issues of female infertility.

Reproductive physiologist Andrea Cupp and colleagues in the Department of Animal Sciences advance the understanding of bovine reproductive biology using advanced genetic analysis, reproductive tissue culture and other tools.

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

“Cows ovulate one egg each reproductive cycle,” Cupp said. “The length of gestation – the incubation period of a fetus – is similar: nine months. Cows have a similar reproductive cycle, similar endocrine hormones, and similar ovarian size. It is directly applicable to female human conditions.”

Farm animals face significant problems with infertility, Cupp said. An example is anovulation, the lack of release or irregular release of an ovum from the ovary during the reproductive cycle.

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

Cupp and her colleagues found another parallel: A significant percentage of the cows studied by the Husker scientists have symptoms similar to women with polycystic ovary syndrome (PCOS), one of the most common infertility diseases in the United States. PCOS affects between 6% and 11% of American women of childbearing age.

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

Cupp noted that the herd in her study was characterized by the strikingly high androgen levels in many cows, similar to the condition of women 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 identified the cows as a good model for female infertility research. Her Husker colleagues, Cupp said, add significantly to the scope of this study.

Jennifer Wood, Professor of Molecular and Cellular Reproductive Biology, studied PCOS as a postdoc and was a key contributor to the project. Bob Cushman, a research physiologist at the US Meat Animal Research Center at Clay Center, Nebraska, was instrumental in developing techniques for obtaining ovarian tissue for study purposes. Several scientists have contributed to a better understanding of genetic implications: Jessica Peterson, associate professor of animal functional genomics; Matt Spangler, professor and specialist in bovine genetics; and Melanie Hess, quantitative geneticist and research assistant professor.

Recently, Ligia Prezotto, a neuroendocrinologist and research assistant professor, joined the team to study how a mother’s exposure to elevated hormones during pregnancy can rewire the fetus’ brain differently and contribute to PCOS-like symptoms.

Scientific research into women’s health, including fertility, has long faced major obstacles because the study of disease and many biological systems has traditionally used male animal models rather than females.

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Due to the complications caused by the female reproductive cycle, it is more difficult to study female physiological processes. However, these hormonal differences during the menstrual cycle in women and the reproductive cycle in female livestock are critical to their health and response to disease and warrant detailed scientific understanding.

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

Specifically, Cupp’s research focuses on factors with the potential to restore proper blood vessel formation in the ovaries, which may promote healthy development of the ovarian follicles that contain the egg. A focus is on vascular endothelial growth factor, a protein that directs cellular signals for a variety of important blood vessel actions.

Her graduate students used the growth factor to treat bovine ovary pieces to see if the protein could promote healthy follicular development. Through this innovative lab approach, “we basically salvaged these follicles and ovarian bits from our androgen-rich cows,” she said.

Cupp noted the important care 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.

Her graduate students, she said, have been by far the project’s best advocates. They worked many hours to ensure that this androgen excess cow model could be used to advance female infertility research in both cows and women.

Andrea Cupp (right) shows Ailenn Castillo, a senior forensic scientist major, how to obtain plasma from blood samples from research cows. Cupp demonstrates the centrifuge process for separating the blood components so that the DNA can be stored and the cows can be genotyped. Eric Buck/Zoiology | courtesy photo
Anteneh Mersha, a doctoral student in the Cupp laboratory, discusses the processing of blood plasma with Andrea Cupp. The Cupp laboratory analyzes the level of the hormone progesterone in blood samples from the research cow herd. Hormone levels relate to when a heifer reaches puberty, which may be linked to infertility. The research findings are relevant to a better understanding of the factors behind infertility in women. Eric Buck/Zoiology | courtesy photo
Andrea Cupp (middle), a professor at the Department of Animal Science Center, points to the screen at fibrosis, a measure of inflammation, in a bovine ovarian cortex. Left is Ligia Prezotto, research assistant professor. At right is Brooke Rudloff, a graduate student from David City, Nebraska. Rudloff is investigating the causes of fibrosis in the ovaries of research cows to improve the understanding of bovine infertility. Eric Buck/Zoiology | courtesy photo

-University of Nebraska-Lincoln

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