Circadian Rhythms

The time has come for circadian rhythms.

Yesterday, three scientists—Jeffrey Hall, Michael Rosbash, and Michael Young—were awarded the Nobel Prize in medicine for their work on circadian biology, which is the field of science dedicated to the internal clock on which our bodies run. The ticking of this 24-hour cycle determines when we get tired and hungry, as well as controlling everything from the (very real) phenomena of jet lag to female ovulation, when we’re more likely to have a heart attack, and the time of day we learn best.

“Their discoveries explain how plants, animals and humans adapt their biological rhythm so that it is synchronized with the Earth’s revolutions,” said the Nobel jury.

What are circadian rhythms?

Circadian rhythms are evolution’s answer to the daily cycle between day and night. Life can be pretty unstable, but if biology on Earth can rely on one thing, it’s that the sun will dependably rise and set every day. If you can anticipate change, you can get ahead of it, so early life forms adapted to predict when it would get lighter and hotter, and when it would get darker and cooler over a 24-hour cycle. That meant less sunburns (which are lethal when you’re only one-cell big), more efficient photosynthesis, and eventually the ability to anticipate the activity of your predators or prey.

Fast forward a few millennia, and it also meant our human bodies evolved with genetic clocks inside each cell. One of the biggest challenges for large organisms like us is making sure all our internal clocks run in sync with one another. This coordination allows female pituitaries and ovaries to match up when triggering ovulation; our pancreas, gut, and hypothalamus to link up to make us both hungry and ready to digest; and sleep to be timed to when our muscles are ready to cool down and enable healing, as well as when our brains are most free for maintenance and memory formation.

Well, that’s how nature had worked it out, anyway. In the 21st century, we’ve messed up that internal coordination with things like artificial light, fast-food binges at 2am, shift work, and early college-class schedules. These forced schedules mess with our body’s natural ebb and flow of when we should be sleeping and eating according to where the sun is in the sky, and it’s wrecking havoc on our systems.

Circadian disruptions are likely contributors to the obesity epidemic, the US’s cancer rates, the autism epidemic, the increase in Alzheimer’s and other dementias, and the growing dissatisfaction within public education. Because every part of our body has been imbued with an innate circadian rhythm to keep all the clocks ticking in sync, every piece of us is susceptible to circadian disruption.

hings that are controlled by our circadian rhythms

To give you an idea of how pervasive circadian biology is to our lives, here’s a quick list of the ways it affects us:

Jetlag: When the time of day suddenly artificially changes, some of your organs catch up faster than others. During this adjustment period, your insides are aligned to different clocks running at different speeds. As a result, they can’t do their jobs as well, and you feel funky (or fall asleep in the back of cabs).

Fertility: Your sex drive has a circadian rhythm, and so do your sex hormones. For example, ovulation is under circadian control to happen in the early morning. I’m told that this was first documented when IVF was invented in France and they found women flying in from the States had lower success rates: Turns out jetlag was messing with their ovulation! (By the way, so does shift work.)

Mental focus: You learn best at a time of day—but that optimum few hours is different for everyone. New brain cells, new synapses, sleep, and attention are all regulated by the time of day, so keeping a routine keeps them razor-sharp. (Fun fact: When you learn something, it gets a circadian time-stamp, and you recall it best at that time. So it’s always best to practice at the same time of day as you’ll perform.)

Nutrition: Circadian rhythms don’t just control when you get sleepy: They control when you get hungry, too. Just as your body absorbs information differently at different times of the day, it does the same with food. For example, at night, food converts into fat more readily than it does during the day.

Heart attacks: Your heart is used to dealing with stress during the day—there’s a lot to be anxious about nowadays, after all—but it recovers at night. As your body ramps up during the morning, your heart, still chilling out, gets strained, so most heart attacks occur in the early morning.

Aging: Finally, as you get older, your body has more trouble holding all of these rhythmic pieces together. The more they fall apart, the more your risk of age-related maladies increases. Getting bright sunlight in the day and having a dark, quiet space to sleep can help keep your circadian rhythms robust—and keep you alive longer.

The importance of circadian biology

And we wouldn’t know a lot of this if it weren’t for Hall, Rosbash, and Young. These newly minted Nobel laureates first showed that internal clockwork could be mapped on a schedule, which seeded an exponential expansion in time-focused biological discovery. The reason science on circadian rhythms has grown so substantially is that each time a biomedical field of science integrates circadian biology, every part of that field has to be re-examined to take the time of day into account. Compare this to fields not yet kissed by the circadian method, where samples are taken whenever it’s convenient for the researchers and lumped together in one, time-vague data point. This blurs variability across the day. Circadian biology is therefore an ever-growing library, in which these men wrote the first several mechanistic volumes.

This re-examination of other scientific fields through the lens of circadian rhythms has heralded the construction of “chronotherapy” in the medicine industry. If a drug is most toxic at a certain time of day, but most effective at another time of day, then timing the dose can mean you use smaller amount of the drug, get more bang for your buck, and have fewer side effects. This has made a big impact in cancer treatment and sleep therapy, for example, but it’s full potential is still in its early days.

We now also know that our circadian profiles are personal. Just as there is not one food that can grow a healthy society (I’m looking at you, refined flour), when it comes to going to bed or eating breakfast, there is not one time that works for everyone. Trying to hold on to old models forces a lot of people to suffer circadian disruption, which is both bad for their wellbeing in the moment and can potentially implicate their future medical costs. I believe we might come to optimize social obligations like work and school around individuals, because the alternative will be shown to be abusive to our individual biological makeup.

Another personalized area we’ll see changes in will be predictive medicine. When you track changes in a biomarker over time—such as blood pressure or cortisol levels—you can detect the deviations from your normal baselines not just for that day, but for that specific time of day. When something in your body changes—like getting sick or becoming pregnant—the shape of your biological day changes, too. Some chronobiologists are working to build predictive algorithms based on detecting personal deviations from the normal shape of the day, and using those deviations to predict future changes.

In research, we've found patterns for predicting cancer and surgical recovery, detecting pregnancy and predicting pregnancy outcomes, and for monitoring fertility, sleep, stress, and learning. Others in my field are predicting sepsis in hospitals and identifying people at risk for Alzheimer’s Disease—and helping them stave it off by strengthening their circadian rhythms. This predictive medicine, based on time-series analysis, will be cheaper, more accurate, and more personal that medicine could otherwise be.

There is still a mountain of work ahead of us before the world is optimized around its biological timing. But because of these Nobel laureates, and the attention their work will now be given, we finally might all get on the same rhythm.


Up to 7 years of hormone therapy is safe for postmenopausal women, new data show


For decades now, women navigating menopause have been buffeted by shifting research findings on the risks and possible benefits of hormone-replacement therapy. Now, a landmark clinical trial that followed more than 27,000 subjects for roughly 18 years has offered some conclusive evidence that neither the hype nor the grim warnings about hormone-replacement therapy were warranted.

In findings published Tuesday in the journal JAMA, women who were randomly assigned to take some form of hormone-replacement therapy for a median of six to seven years were no more, nor less, likely to die of any cause over the study’s duration than were women who had been assigned to receive a placebo treatment.

The women who got synthetic estrogen and progesterone hormones to replace their naturally declining levels were no more (nor less) likely than those who got a placebo to die of stroke or heart failure. And they were neither more nor less likely to die of cardiovascular disease or cancer.

University of Pittsburgh Dr. Melissa McNeil, who wrote an editorial appearing alongside the new findings, called them “both compelling and reassuring.”

For women who enter menopause early, whose bones are at high risk of fracture, or who suffer menopause-related hot flashes, night sweats and sleep disruption, “hormone therapy appears to be both safe and efficacious,” wrote McNeil, who directs the comprehensive womens’ health program at Pitt’s general internal medicine division.

The findings come from the Women’s Health Initiative’s hormone therapy trials, which were launched to assess the benefits and risks to mostly healthy post-menopausal women of taking hormone-replacement pills in a bid to reduce their risk of developing such cardiovascular and other chronic diseases. The study’s 27,347 subjects averaged about 63 years old when they joined the study.

The Women’s Health Initiative has been the source of a number of findings on the safety of hormone replacement therapy, many of them more perplexing than enlightening. In 2002 and 2004, its findings raised concerns that HRT would increase women’s risk of heart disease, stroke and breast cancer.

Those findings would eventually lead to safer hormone combinations and a better understanding of who should consider HRT and when it should be initiated. But they would also slow a gathering stampede of menopausal women toward HRT and discourage many who could benefit from the treatment from considering it.

The latest trial results compared the death rates of 13,531 women who were assigned to take a placebo treatment to those of menopausal women who got one of two different forms of hormone-replacement therapy: 8,506 women — mostly those with an intact uterus — were assigned to get a combination of estrogen and progestin, and 5,310 — most of whom had undergone hysterectomy — got estrogen alone. (For women with an intact uterus, progestin was widely added to HRT regimens in the 1980s and ’90s after researchers found that estrogen-alone regimens increased rates of endometrial cancers in such women.)

Over the trial’s 18 years of follow-up, 7,489 of the women died. But whether researchers looked at death-from-any-cause, or deaths due to cancer, heart disease or stroke, the distribution of deaths in the trial’s various arms showed no statistically significant differences.

While those findings will probably reassure women who have avoided taking replacement hormones for menopausal symptoms, they are likely as well to temper claims that HRT can help women reduce their risk of certain diseases and prolong life.

The findings, the new study’s authors flatly wrote, “would not support use of hormone therapy for reducing chronic disease or mortality.”

The results of the new trial, which represents the largest and most comprehensive study to assess HRT’s effects, are in line with a position statement on HRT issued in June of this year by the North American Menopause Society.

That statement — the product of a comprehensive review of research by NAMS leaders — concluded that for most women who initiate hormone replacement therapy under 60, or within 10 years of reaching menopause, it’s safe and can improve quality of life, increase productivity and reduce medical expenditures linked to untreated symptoms of menopause.

“This study is just one more piece of reassuring data in line with our findings,” said Dr. JoAnn V. Pinkerton, professor of obstetrics and gynecology at the University of Virginia Health Center and chair of the NAMS panel that drafted that position statement.

In the wake of the first Women’s Health Initiative findings issued 15 years ago, said Pinkerton, “fear drove women’s decisions” on HRT. That should now change, she added — especially since safer and lower-dose HRT formulations are now available to women.

Pinkerton, who was not involved in the new research, acknowledged that women should not initiate hormone replacement therapy in hopes of fending off heart disease, dementia or osteoporosis. But despite the current study’s failure to find survival benefits in those who took HRT, Pinkerton said women who are considering treatment because they’re troubled by hot flashes and menopausal symptoms should know they might get some protection.

“There’s a critical window” during which other research suggests the initiation of hormone replacement “appears to have benefits for heart, brain and bone,” Pinkerton said.

Hormone Therapy Isn’t As Risky As Once Thought, New Study Finds


Scientific opinion on hormone replacement therapy sometimes feels like a pendulum that swings back and forth, leaving women confused about what treatment for menopause symptoms, including hot flashes, vaginal dryness and osteoporosis, is best for them.

While all medical treatments pose some risk, are the risks of treating menopause symptoms worth the benefits that hormone replacement therapy (HRT) can deliver? That’s the question that women have been asking and hoping that research clarifies.

Maybe it’s time for them to relax, a new study suggests.

In a new randomized study of 27,347 women who were followed for 18 years, those who took hormone medication were no more likely to die of any cause than women who were given a placebo.  

The Women’s Health Initiative hormone therapy trials tested the most common types of hormone therapy ― estrogen alone and estrogen plus progestin ― to assess the benefits and risks of menopause hormone therapy taken for chronic disease prevention by predominantly healthy postmenopausal women.

Researchers analyzed data from two trials, which included postmenopausal women with an average age of 63 at enrollment, and explored the effect of treatment over five to seven years, with 18 years of cumulative follow-up, and then defined the effect of hormone therapy on mortality rates. 

All-cause mortality provides a “critically important summary measure” for an intervention such as hormone therapy that has a complex matrix of benefits and risks, said lead author JoAnn E. Manson, a professor at Harvard Medical School and a past president of The North American Menopause Society.

“Mortality rates are the ultimate ‘bottom line’ when assessing the net effect of a medication on serious and life-threatening health outcomes,” she told HuffPost.

The team also found that deaths from Alzheimer’s disease and other forms of dementia were significantly lower with estrogen-alone medication than with a placebo during 18 years of follow-up.

Women and doctors should be reassured.

Hormone therapy, while unquestionably effective in reducing hot flashes and other menopause symptoms, has also been linked to serious health risks including blood clots, stroke and certain cancers. “In this new analysis, we found that there was no association between hormone therapy and all-cause mortality during either the treatment period or the long-term follow-up of these trials,” Manson said.

In this study, participants were assigned randomly to separate groups to compare different treatments. By using this randomization method, the groups were guaranteed to be similar and the treatments could be compared objectively. Other studies were conducted differently.

Manson said that her team’s findings support clinical guidelines that endorse the use of hormone therapy for recently menopausal women to manage hot flashes and other symptoms. 

Overall, she told HuffPost, the findings should reassure women and their doctors that hormone therapy is a reasonable option for symptomatic women who are in early menopause and in generally good health. 

Still, it is confusing to know which study is right.

For many women, just the act of processing all the seemingly conflicting findings on the value and risks of HRT can be confusing.

Many hark back to the 2002 Million Women Study in Britain, which shook women to the core when it proclaimed that HRT was potentially harmful and caused a higher risk of fatal breast cancer. 

A year after that study came another that linked taking estrogen plus progestin to an increased risk of dementia. That study, too, concluded the HRT combination presented risks that outweighed its measured benefits.

The multiple studies suggesting that potential harm outweighed the benefits of hormone therapy led to a swift decline of its use throughout Europe and the U.S.

Sales of hormone therapies fell by 50 percent from 2002 to 2005 as women got the message that HRT caused more problems than it solved. Increased risks of breast cancer, heart disease, stroke and blood clots were just some of the problems researchers documented in women who used HRT.

The medical community has modified its views about the role of hormones as more research has been conducted. Experts agree that there is much they still have to learn, said The North American Menopause Society. 

Joann Pinkerton, director of the NAMS, says the group recommends not limiting hormone therapy to the lowest dose or shortest duration but instead to find the most appropriate hormone therapy for each woman. 

There are many newer options, including transdermal patches, with potentially less risk of blood clots or stroke, she said.

The research was published Tuesday in JAMA.