Insights Into the So-Called Diapause Can Advance Our Understanding of Female Infertility

Oxytocin, a hormone already known for its role in childbirth, milk ejection and mother-infant bonding, may have a new role in mammalian reproduction. In times of maternal stress, the hormone can delay the development of an embryo by days to weeks after conception, a new study in rodents shows. According to the authors, the findings on what is known as “diapause” could offer new insights into pregnancy and fertility problems in humans.

What is Diapause?

led by researchers at NYU Langone Health, the study examined diapause, in which an embryo in the early stages of development temporarily halts its growth before attaching to its mother’s uterine lining, a crucial step that leads to the formation of the placenta. Observed in species as diverse as armadillos, giant pandas, and seals, diapause is thought to have evolved to help expectant mothers conserve scarce resources (e.g., breast milk) by delaying birth until they have enough to successfully care for their offspring.

Although recent studies have found evidence that a form of diapause can also occur in humans, the underlying mechanisms have remained unclear. The results in mice showed that one type of stress that can cause a diapause is milk production and delivery (lactation), because during lactation, the mother releases nutrients from her body to offspring that have already been born and are growing in the womb. The study found that the time between conception and birth (gestation) – which is normally 20 days in these animals – was delayed by about a week in pregnant rodents that were already nursing a litter. Furthermore, the research team showed that this delay was caused by an increase in oxytocin production, the levels of which are known to rise when a mother is lactating.

The Role of Oxytocin in Infertility, Premature Birth and Miscarriage

To confirm this role for the hormone, the researchers exposed mouse embryos to a single dose of oxytocin (either 1 microgram or 10 micrograms) in the laboratory and found that even these small amounts delayed their implantation in the uterus by up to three days. The team found that not only did pregnancy stop, but that fluctuations in the hormone large enough to mimic the levels and timing measured during lactation resulted in pregnancy loss in almost all cases in mice. “Our results shed light on the role of oxytocin in diapause,” said co-author of the study, Dr. Moses Chao, professor in the departments of Cell Biology, Neuroscience, and Psychiatry at the NYU Grossman School of Medicine. Based on this newly discovered link, it is possible that abnormalities in the production of this hormone play a role in infertility, premature birth, delayed birth, and miscarriage.”

In another part of the study, the team looked for a mechanism that allows embryos to respond to an increase in oxytocin. The researchers found that the hormone can bind to special proteins, called receptors, on the surface of a layer of cells known as trophectoderm, which surrounds the early embryo and eventually forms the placenta. In particular, mouse embryos that had been genetically modified to lack oxytocin receptors lived long enough to implant into their mother’s placenta in much smaller numbers than normal embryos. This suggests that the ability to respond to oxytocin spikes and thus enter diapause is somehow important for the survival of the developing offspring, says Chao, who would like to investigate this protective function in more detail.

How these Findings Could be Applied in Reproductive Medicine

“Although infertility and developmental problems that can occur during pregnancy are very common, they are still poorly understood and can have devastating effects on parents and their children,” said senior study author Dr. Robert Froemke. A deeper understanding of the factors that contribute to these problems could enable experts to better address them in the future,’ added Froemke, who is the Skirball Professor of Genetics in the Division of Neurosciences at the NYU Grossman School of Medicine. Froemke is also a professor in the Department of Otolaryngology – Head and Neck Surgery and says the researchers next want to study how cell growth is re-established after diapause.

The team also wants to explore how diapause can affect the health and development of offspring after birth, and find out whether and how their discoveries can be applied to reproductive medicine. Froemke cautions that while the study results are promising, mice and humans, though both mammals, have significant differences in their reproductive processes. He adds that the current research did not address the role that other pregnancy-related hormones, such as estrogen and progesterone, might play in diapause.