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Off the Clock: Disrupted Daily Rhythms Hinder Fertility in Mice

Mice whose sleep patterns were altered had more difficulties conceiving and carrying pregnancies to term. The findings may have implications for women trying to conceive



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“My biological clock is ticking.” The phrase typically pops up in movies about middle-aged women who want to start a family before menopause makes it impossible. But a new study published May 23 in PLoS ONE indicates that another clock may also be important for females trying to conceive: the one that regulates our waking and sleeping cycles. 

A strong body of evidence links daily wake-sleep cycles to feminine reproductive cycles. When scientists remove a female mouse’s suprachiasmatic nucleus—the pacemaker in her brain that regulates daily circadian rhythms—her estrous cycle ceases, and she becomes infertile. In human females, working night shifts and frequently traveling across time zones has been associated with menstrual irregularities, reduced fertility and a greater number of negative pregnancy outcomes such as low birth weight, preterm birth and miscarriage.

But “one of the issues with these epidemiological studies,” says Keith Summa, a medical and doctoral student at Northwestern University, “is that there are other factors associated with shift work that may also be playing a role.” For example, women who work night shifts also tend to sleep less. “Our study provides stronger evidence that reproductive problems are due to circadian disruption itself,” Summa says.

Summa and his colleagues divided a group of 48 inseminated female mice into three groups. Then they fiddled with the rodents’ sleep patterns by changing the lighting conditions in the cages. The control mice experienced a normal light-dark cycle: 12 hours of “daylight” and 12 hours of “nighttime,” on a set schedule that never wavered.

The researchers shifted the light-dark cycles for the two less-fortunate groups of mice.  In one cage, the morning lights went on progressively later; mice began the experiment with a “daytime” of 6 a.m. to 6 p.m., but then after five days, researchers shifted the light forward by six hours, so that daytime would last from noon to midnight instead. The five-day period allowed the mice to adjust to each new schedule before it shifted again.

In the third cage, mice received the reverse treatment: the lights were turned on progressively earlier. For these mice, if “daytime” started at 6 a.m. during the first five-day period, it would begin at midnight during the next period, and so on.

The five-day shifts occurred over 25 days. By the end, 90 percent of the mice that were kept on a consistent light-dark schedule carried full-term pregnancies. In contrast, mice exposed to daylight that shifted forward had successful pregnancies 50 percent of the time, and the animals exposed to daylight that shifted backward had a success rate of only 22 percent.

“The degree to which it affected fertility was surprising,” says Tamara Varcoe, who studies circadian rhythms at the University of Adelaide in Australia and was not involved with the research. “They show very profound effects just from doing a relatively minor intervention.” She and Summa agree that the next step is to determine exactly when and why the fertility losses occur.

“We didn’t see evidence of late loss of pregnancy, suggesting effects are occurring early on,” Summa notes. He suggested that maybe the circadian disruptions prevent embryos from implanting in the uterine wall.

Last year, Varcoe’s lab disrupted the circadian rhythms of pregnant rats, but didn’t observe fertility impacts. Importantly, Varcoe’s group began adjusting the light-dark cycle after the rats were confirmed pregnant, whereas Summa’s group began immediately after insemination. Varcoe agrees that the fertility losses that Summa observed may be due to embryo implantation problems.

“Clocks appear in all the tissues of our bodies,” Varcoe explains. “Rhythmic clock genes are expressed in pregnant and non-pregnant uteri, but we don’t really know what they do. There are many other factors that a fetus gets exposed to, including hormonal rhythms from the mother.”

So should a pregnant mother quit working the night shift, or stop flying cross-country? Not so fast: it’s not easy to translate results from animal models into medical advice for people, says Michael Katz, a doctor who works for March of Dimes (which helped to fund the study). Human and mouse reproductive cycles are similar—both species have estrous cycles that are guided by the circadian clock—but there are subtle differences. Mouse estrous cycles last only four days, for example, and mice do not menstruate.

Nevertheless, the results suggest that “if a woman is working at unusual hours, and is trying to get pregnant and can’t, perhaps this is something she should look into,” Katz says. He says that women can still work night shifts and have healthy pregnancies-- the main thing is to be consistent.

Summa agrees. “What we can suggest,” he says, “is that for women who are trying to conceive, it’s probably beneficial to maintain good sleep cycles. They should go to sleep at about the same time every day, and get plenty of sleep.” And because circadian disruptions have been linked to many health problems—including obesity and diabetes, bipolar behaviors, and depression—that may be good medical advice for everyone.
 

 

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