Volume 4, Issue 29 July 2007
Keeping the Body On Schedule
Lance Kriegsfeld studies how the body's master clock coordinates systems ranging from hair growth to food digestion. photo courtesy of Lance Kriegsfeld
Hours before you wake, an inner alarm clock primes your body for a day on the go. From deep within your brain, it triggers the release of hormones that tell your cells to mobilize sugars, your blood pressure and temperature to rise, and your gut to make the enzymes that will break down breakfast. The rise and fall of these and other hormones throughout the day keep the body's systems working in harmony.
"Hormones are controlled on a daily or circadian schedule and this timed secretion has important implications for health and functioning," says UC Berkeley Professor of Psychology and Neuroscience Lance Kriegsfeld. "No matter what you look at, whether daily rhythms in cognitive function or testosterone, every system is controlled in a very precise manner with a peak at a certain time of day and a trough at another."
Anyone who has experienced the fatigue and insomnia of jet lag knows that messing around with the internal clock is bad news for the body. These troubles are magnified among the estimated 20 million Americans who work irregular or evening shifts. For example, female shiftworkers have a higher incidence of breast cancer, have more difficulty becoming pregnant and maintaining pregnancies.
Kriegsfeld is interested in how the brain's clock affects hormone cycles in the body. Kriegsfeld's current research determines how the body clock controls ovulation. His findings not only could help more women conceive but may also help make jet lag a thing of the past.
The suprachiasmatic nucleus (SCN) is the timekeeper that coordinates many bodily functions. It is located deep within the hypothalamus in rodents as well. image: Lance Kriegsfeld
In many creatures, the body clock controls ovulation with an iron fist. Hamsters, for example, "ovulate every 96 hours on the dot," says Kriegsfeld. Among humans, the circadian clock plays a more muted role. Work schedules and stressful family situations can dim its effects. "Yet even in humans, it's playing a role," says Kriegsfeld. "Stewardesses and other female shift workers with irregular schedules and sleep habits typically do not have normal menstrual cycles, indicating that there's circadian participation."
Ovulation occurs when a portion of the brain called the hypothalamus releases a substance called gonadotropin-releasing hormone, or GnRH. GnRH, in turn, triggers the pituitary gland to turn on a hormone that fosters egg production.
As eggs mature in the ovary, they release ever larger doses of the hormone estrogen. Throughout most of the reproductive cycle, estrogen tells the brain to keep GnRH production at a trickle. But at a critical level, estrogen suddenly switches roles: it goes from suppressing GnRH production to somehow turning it on again.
But after years of study, scientists still cannot explain this phenomenon. "To date, a cellular mechanism by which this switch occurs has not been found," Kriegsfeld says.
In 2004, scientists led by Kazuyoshi Tsutsui of Hiroshima University, Japan, announced they had isolated a hormone that was the antidote to GnRH in Japanese quail. For this reason, they called the molecule gonadotropin inhibitory hormone, or GnIH.
The brain clock, or SCN, controls the timing of ovulation. At the start of the cycle, SCN neurons trigger the release of the hormone GnRH. GnRH triggers the pituitary to manufacture other hormones (LH/FSH) that stimulate the ovaries to ripen an egg. Estrogen released by the maturing egg keeps the cycle on hold until ovulation. image: Lance Kriegsfeld
Kriegsfeld speculated that GnIH might be the missing link in the ovulatory process. He teamed up with Tsutsui and George Bentley, a professor of integrative biology at UC Berkeley, to tackle this question. By labeling GnIH neurons with a fluorescent tag, Kriegsfeld and colleagues were able to trace the hormone's origins and path of travel within the brains of rodents. They found that GnIH is made in neurons of the hypothalamus, and that these same neurons communicate directly with cells that manufacture GnRH. These studies suggested that GnIH might act as the brakes on the reproductive system until the time of ovulation.
Together, these findings suggest that estrogen from a developing egg encourages production of GnIH. GnIH then suppresses the manufacture of GnRH. Only when estrogen levels peak, indicating the egg is ripe, does GnIH fade, Kriegsfeld's current research suggests. Its disappearance allows GnRH production to resume and start the cycle all over again.
"Now we have a system that seems to be the missing link in the chain of events controlling ovulation," Kriegsfeld says. Kriegsfeld's present research investigates how the circadian clock might lift the brakes of GnIH to allow ovulation to occur.
More recently, Kriegsfeld, in collaboration with Gregory Demas, a professor of biology at Indiana University, has begun to examine yet another player in the system, a protein called kisspeptin. Kisspeptin acts like gasoline on the fire of the brain's reproductive system, accelerating the production of GnRH. They are now studying whether kisspeptin also plays a role in initiating ovulation.
"If we could get a handle on how hormone secretion is controlled over time, we could optimize body functioning for people with normal work schedules. We could also ameliorate the symptoms of jet lag for people who are forced to fly frequently or work odd hours," Kriegsfeld says. "Since hormones are in a position to talk rapidly to so many cells throughout the brain and body, they could be utilized as a mechanism for resynchronizing our physiology."