Researchers enroll sheep to control common fertility disorder

A Texas A&M AgriLife study with sheep may soon help address fertility problems in women, if it can discover ways to break the chain of generational transfer of polycystic ovary syndrome (PCOS) – one of the most common infertility disorders. 

Dr. Rodolfo Cardoso, a veterinarian and Department of Animal Science assistant professor and reproductive physiologist in Texas A&M’s College of Agriculture and Life Sciences, will lead a $2.4 million National Institutes of Health-funded project which will investigate the multi-generational effects of prenatal exposure to androgen excess using the sheep as the animal model. 

Joining Cardoso on this project are Dr. Renata Landers, a post-doctoral research associate in Cardoso’s program, Jessica Sustaita, a graduate student in Cardoso’s team and Dr. Vasantha Padmanabhan, a professor in the Department of Pediatrics with the University of Michigan Health System who will also serve as a principal investigator in the project. 

PCOS affects about five million women in the U.S. and over 100 million women worldwide. It is a complex syndrome with an increased risk of cardiovascular disease, dyslipidemia, hypertension, diabetes mellitus and endometrial cancer. 

Findings from this sheep model will provide crucial biological information for improving reproductive function across generations and are of clinical relevance to women with PCOS and other hyperandrogenic fertility disorders. 

Choosing sheep 

A critical concern of PCOS is the vertical transmission of unwanted traits to the offspring. A woman who has PCOS is highly likely to pass the disorder to her daughters and granddaughters, according to Cardoso. Sheep are very similar in which the daughters of ewes with PCOS also typically have the syndrome. 

“The sheep is an animal model which is very translational to humans,” Cardoso explained. “When we look at what happens during fetal life, the development of the ovine fetus parallels the development of humans.” 

He continues, “While much of biomedical work uses rodents in research, our ability to translate our findings are much easier and clinically relevant to humans when using sheep. Other key benefits are sheep only generate one or two fetuses, not a litter, and they have a gestation process more similar to humans.” 

Approximately 70 percent of women with PCOS are obese or overweight with metabolic complications, he said. It is well documented if women are able to lose weight and improve metabolic function, they can improve their fertility.  

It is also known whatever happens to a baby during fetal development can affect the health of the individual throughout their life and can also carry over to the next generation upon reproduction. 

“What we are trying to answer with this project is how to break this multi-generational cycle using dietary interventions,” Cardoso said. “The goal is to prevent the animals from becoming obese and thus prevent the vertical transmission of PCOS traits.” 

It would take 20 or more years to answer the question in humans. The dietary changes would be made with the mother while she was carrying the fetus, but then would require waiting until the daughter grows up and has a daughter. 

“With sheep, we can answer the question much quicker,” said Cardoso. “Within three years, we will have the daughter reaching puberty and soon have a granddaughter present so we can investigate the effects of the dietary interventions.” 

Cordoso said the mothers received an androgen treatment during pregnancy. The androgen treatment mimics the conditions or disease occurring in humans which elevate their level of steroid hormones during pregnancy, such as PCOS and congenital adrenal hyperplasia.  

The androgen levels in humans can also be raised during pregnancy in other situations such as when women who are unaware they are pregnant continue to take contraceptive pills or after exposure to environmental compounds acting in a similar way to steroid hormones, notes Cordoso. 

“We know these sheep will have PCOS and we know when their daughters reproduce, they will develop PCOS. We will do the dietary intervention with those daughters and then study the granddaughters,” Cardoso said. 

Beyond the diet 

In the first four years of this study, Cardoso said he plans to use dietary interventions or lifestyle modifications to improve the health of pregnant females and then track multi-generational impacts to understand if it worked and if the lifestyle interventions help. 

The final year of the study will concentrate on epigenetics studies, identifying mechanisms by which prenatal androgen exposure as well as dietary interventions can control how specific genes are expressed, Cordoso noted.  

“We know diet plays an important role in the cross-generational expression of genes,” he said. “We know in humans lifestyle intervention will improve PCOS. But, what we don’t know is if we can minimize the risk of PCOS being passed to daughters and granddaughters. If we learn the mechanisms of how the diet is improving the health, we may identify therapeutic targets for improving health and fertility in women with PCOS.” 

This article was written by Kay Ledbetter and is courtesy of Texas A&M AgriLife. For more information, visit agriliferesearch.tamu.edu.