Oregon Health & Science University researchers have developed a new lab model to study how changes in cervical mucus during the menstrual cycle help regulate fertility. This model could help develop new, non-hormonal birth control methods for women.
The study, published in the journal Biology of Reproduction, is part of ongoing work by senior author Leo Han, M.D., M.P.H., associate professor of obstetrics and gynecology in the OHSU School of Medicine and the OHSU Oregon National Primate Research Center. Han is a complex family planning specialist whose research focuses on developing new, non-hormonal contraceptives.
In this study, his research team analyzed the genetic activity in lab-cultured cervical cells, identifying hundreds of different genes that could be drug targets for birth control that uses innovative new methods to block sperm.
Of the 45% of unintended pregnancies that happen annually in the U.S., Han said, more than 95% are from people not using contraception, or using it incorrectly or inconsistently.
"There are a lot of people who don't want to be pregnant, but won't, or can't, take hormonal birth control," he said. "The cervix is the gateway to fertility. Sperm must pass through the cervix to reach the uterus and then the fallopian tubes where fertilization occurs. So, there is a natural chokepoint, so to speak, where you can create a barrier at or in the cervix."
Katrina Rapp, M.D., lead author of the study, was an OHSU medical student at the time of the research and is now a resident in obstetrics and gynecology at OHSU.
"Throughout medical school, I focused on understanding and addressing unmet contraceptive needs experienced by individuals in the U.S.," she said. "I have had numerous conversations with women who desire a non-invasive, non-hormonal contraceptive option, and cervical mucus serves as an ideal target for such a method, due to its ability to naturally regulate fertility throughout the menstrual cycle."
Powerful new tool
The mucus in the cervix plays a vital role by allowing sperm to enter the reproductive tract only during a woman's fertile window, around ovulation. During this time, high levels of estrogen make the mucus thinner and less viscous, allowing sperm entry. After ovulation, when pregnancy is no longer likely, progesterone thickens the mucus to prevent sperm and harmful pathogens from entering the upper reproductive tract.
"The changing mucus is key to reproduction," Han said. "During ovulation, mucus becomes watery and there is a lot of it. It makes for a slip-and-slide for sperm to enter, as opposed to other times when the mucus has the consistency of rubber cement or an extremely thick honey. In this study, we are trying to understand how cells make mucus differently during those different time points."
This cyclical change in mucus is a natural part of the menstrual cycle. Cervical mucus is produced by a layer of cells lining the cervix called columnar epithelial cells. These cells produce a combination of water, proteins and mucins, which are large proteins that give mucus its gel-like consistency. One key protein in cervical mucus is MUC5B, which helps form the gel that changes throughout the cycle. Other factors, like ion channels, also play a role in how mucus behaves, altering hydration and helping the mucus change its consistency. Abnormalities in these ion channels can lead to problems with mucus production, which could affect fertility or increase the risk of infections.
To study this process in more detail, scientists developed an in vitro, meaning lab-based, model using cells from rhesus macaques, which has a cervix similar to humans. They grew those cells and then treated some with hormones.
The researchers used RNA sequencing to analyze the genetic activity in the cultured endocervical cells. This allowed them to identify the genes and pathways that regulate the production of mucus during the menstrual cycle. They focused on how hormones influence the synthesis of mucins, hydration of mucus, the stabilization of mucus structure, and other important processes.
"One of our major findings is we identified about 150 different genes in one group, and 250 in the other, and they were substantially different under those different conditions," Han said. "They represent potential drug targets or potential explanations for what is happening when the mucus is changing."
This new in vitro model offers a powerful tool for studying cervical mucus in a controlled environment, helping researchers uncover the molecular mechanisms that regulate fertility and how different hormones impact reproductive health. The research team is next testing non-hormonal inhibitors of fertile mucus production in nonhuman primates.
"With unmet contraceptive needs and the consequences of unplanned pregnancy disproportionately affecting marginalized and socioeconomically disadvantaged populations, this field of research has the potential to promote and protect reproductive justice," Rapp said.
In addition to Han and Rapp, OHSU medical school and primate center co-authors include Shuhao Wei, B.S., Mackenzie Roberts, M.S., Shan Yao, M.D., Suzanne Fei, Ph.D., Lina Gao, Ph.D., Karina Ray, M.S., Alexander Wang, B.S., and Rachelle Godiah, M.P.H.
This research was supported by the National Institutes of Health's Reproductive Scientist Development Program by the National Institute of Child Health and Human Development Grant K12 HD000849, March of Dimes Foundation, American Society for Reproductive Medicine, and American Board of Obstetrics and Gynecology as part of the RSDP, OHSU School of Medicine, Medical Foundation of Oregon, and Office of the Director, of the National Institutes of Health under Award Number P51OD011092. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.
All research involving animal subjects at OHSU must be reviewed and approved by the university's Institutional Animal Care and Use Committee (IACUC). The IACUC's priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value and justify the use of live animals.
