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Paper of the Month: Potential for non-hormonal contraception

About the School of Medicine Paper of the Month

The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Senior Associate Dean for Research Mary Stenzel-Poore, Ph.D., Associate Dean for Clinical Science Eric Orwoll, M.D., and Assistant Dean for Basic Research Mary Heinricher, Ph.D.

June’s featured paper is from the labs of Richard Stouffer, Ph.D., senior scientist at the Oregon National Primate Research Center and professor of obstetrics and gynecology/physiology and pharmacology, and Jon Hennebold, Ph.D., associate scientist at the Oregon National Primate Research Center and associate professor of obstetrics and gynecology/physiology and pharmacology. It is titled “A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.” It was published in Human Reproduction.


July 2, 2014

The 20th century has seen the development of many effective methods of birth control. Hormonal contraceptives, whether administered by pill, patch or injection, are commonly used forms of birth control. The effect of hormonal agents on the reproductive system is complex, but birth control generally works by preventing ovulation. However, many concerns remain regarding their side effects and long-term use. Specifically, widespread actions of hormones could have unintended consequences in non-reproductive tissues.

The team of Dr. Stouffer and Dr. Hennebold is developing a better understanding of the molecular mechanisms that drive ovulation. “We are interested in learning if blocking events in the mature follicle of the ovary can prevent the release of an egg,” said Dr. Stouffer. “If so, an effective non-hormonal contraceptive could be developed.”

Previous studies by the ONPRC group and others discovered that a specific class of compounds known as prostaglandins is critical for ovulation in a wide range of animal models. “Prostaglandins, particularly a type called PGE2, coordinate the cellular activities that ultimately lead to the release of an egg from the ovary that is capable of being fertilized,” said Dr. Hennebold.

 

Stouffer

In collaboration with researchers at Bayer HealthCare Pharma, in Berlin, Germany, Drs. Stouffer and Hennebold published their findings in this recent paper. Mary Heinricher, Ph.D., assistant dean for basic research, chose this paper, lauding the work of Dr. Stouffer and colleagues. “This was a very well thought-out and elegant set of experiments, with exciting outcomes,” she said.


Raising the possibility

The research was primarily performed by Marina Peluffo, Ph.D., a postdoctoral fellow who was supported by a fellowship from the Lalor Foundation. Dr. Peluffo and colleagues began by investigating levels of gene expression activity in the monkey ovulatory follicle related to PGE2 synthesis and signaling. They found that the ovulatory stimulus resulted in increased PGE2 synthesis and responsiveness. They then developed a fluorescence-based technique to assess a unique step in ovulation termed cumulus – oocyte expansion or C-OE; use of this assay demonstrated that treatment with PGE2 consistently induced C-OE through the PTGER2 receptor.

Hypothesizing that blocking the PTGER2 receptor would reduce ovulation, the team designed a series of experiments using a selective PTGER2 antagonist.  “Treating female macaque monkeys with this compound blocked the ability of PGE2 to interact with PTGER2, and we observed a significant contraceptive effect,” said Dr. Stouffer. “Notably, steroid hormone patterns or menstrual cycle activity during the trial was not affected.  The treatment was also reversible, with fertility recovered as early as one month after ending the treatment.”

“Importantly,” said Dr. Heinricher, “this work raises the possibility of a completely different approach to pharmacological contraception, one not based on hormones and which could be much more targeted.”


What’s next?

Drs. Stouffer and Hennebold will continue to investigate this nonhormonal contraceptive approach. “Since this protocol was not completely effective, future studies will address the possible role of other PGE2 receptor subtypes in controlling egg release, as well as the optimal doses and mode of delivery,” said Dr. Hennebold. Ultimately, he hopes to develop this research into a nonhormonal contraceptive clinical trial.  “Monitoring as well as improving the efficacy and safety of female contraceptives is an important public health activity,” said Dr. Stouffer. “The development of non-hormonal contraceptives is an important goal for women’s health.”   

Citation

A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.
Hum Reprod. 2014 Apr 29. [Epub ahead of print].
Peluffo MC, Stanley J, Braeuer N, Rotgeri A, Fritzemeier KH, Fuhrmann U, Buchmann B, Adevai T, Murphy MJ, Zelinski MB, Lindenthal B, Hennebold JD, Stouffer RL.

 

Acknowledgements

This research was conducted through the Contraceptive Development and Research Center, which is directed by Drs. R. Stouffer and J. Jensen at the Oregon National Primate Research Center at Oregon Health & Science University. The center is funded by the NICHD and the NIH.


More published papers


Pictured above from left to right:

Jessica Stanley, Richard Stouffer, Jon Hennebold, Mary Zelinski, Tiffany Adevai