Scientists have long considered high levels of the steroid hormone cortisol to be synonymous with stress. Because steroid hormones are derived from cholesterol, they can cross any biological barrier also made of cholesterol, including all cell membranes in the body.
"These hormones have profound effects in that they can go everywhere in the body and even affect the body's genetic material," says Sally Mendoza, a UC Davis psychology professor and authority on the role of cortisol in the stress-regulating system.
In humans and other mammals, a stressful event or situation causes the brain's hypothalamus to release a chemical known as "corticoid releasing hormone" or CRH. Within milliseconds, CRH stimulates the sympathetic nervous system and travels to the pituitary gland to release adrenocorticotrophic hormone or ACTH, which ultimately leads to increased production of cortisol. Some 20 to 30 minutes after the brain first recognizes the stressor, cortisol levels peak.
"For years, researchers wondered how cortisol could be functional so late in the process," Mendoza says. The mystery was solved just a few years ago when Dartmouth physiologist Alan Munck demonstrated that the basic role of cortisol is to turn off all of the other biological processes triggered by the stress.
"Late in the process comes this hormone cortisol that tells the body, 'It's over--if you're still alive,' " Mendoza says.
With each new clue to cortisol's function comes a clearer picture of the relationship not only between environment and stress but also between social conditions and illness, an area that has fascinated Mendoza since the early days of her research career.
"That relationship must in some way be stability-linked," she says. "Our physiology as social animals is dependent on social relationships for health."
To study the importance of relationships in promoting health, Mendoza looked to the small titi monkeys (pronounced tee-tee). Originally from South America, these distant cousins of humans form remarkably strong bonds between males and females.
Separation of male and female titi monkeys results in elevations in cortisol that can persist for weeks. The same reaction occurs in young titi monkeys when they are separated from their fathers, who are the primary caregivers in the family. Unlike other primate species, infant titi monkeys don't form a strong emotional bond or attachment relationship with their mothers, but they do so with their fathers.
"We don't know why in this unusual and very special relationship cortisol doesn't end the stress response," Mendoza says.
Another peculiar type of response to chronic stress was first found in 1985 when Mendoza and William Mason, now a psychology professor emeritus, conducted a study using squirrel monkeys, which usually live in large mixed-sex groups.
In this study, squirrel monkeys that previously had been housed alone were brought together with other monkeys. Such a dramatic change in the social environment might reasonably be expected to be stressful, but there was no stress response in the monkeys and after a week cortisol levels in both males and females noticeably declined.
"I felt like I had come across one of the more important things in my career," Mendoza recalls.
But the question remained: Were suppressed cortisol levels good or bad? To find out, Mendoza and John Capitanio, an assistant professor in the UC Davis psychology department, studied rhesus macaque monkeys infected with simian immunodeficiency virus, the monkey form of AIDS. The researchers daily changed the monkeys' living groups, forcing the animals to continually rebuild their social networks. They found that SIV progressed much more quickly in the test group of monkeys than it did in those monkeys allowed to remain in stable social groups. Interestingly, cortisol levels were much lower among monkeys in the unstable social groups.
"We have no idea why," Mendoza says. "But somehow, lower cortisol levels affect the outcome of the disease. We do know that when cortisol levels are lower than normal, animals have a reduced ability to mount a stress response and therefore cannot adequately deal with environmental changes."
She suspects that both unusually high and low levels of cortisol are harmful, but that a happy medium exists that allows the body to launch a stress response without compromising health. If that's true, the traditional definition of stress must be rewritten.
"Traditionally, we've taken stress to be a response to a threat characterized by high levels of cortisol, but I'm suggesting it's broader," Mendoza says. "Stress is not just the immediate response, but the body's whole regulatory response that is disrupted by chronic changes. It's the disregulation of the system that leads to profound health outcomes."
"Twenty years ago, if you went to a doctor did they ever ask you if you're under stress?" asks Mendoza. "Today you won't find a general practitioner who doesn't think that lifestyle issues are important to health.
"Everybody now knows about stress but nobody knows what it is," she says. "We have to get to the point where my physician can tell me what stress is and how it works."
In the meantime, researchers in related fields are finding plenty of applications for the knowledge gleaned by basic researchers like Mendoza.
"I'm really grateful that other people have done the work of identifying levels of cortisol and other stress indicators," says Carolyn Stull, Cooperative Extension animal scientist in UC Davis' School of Veterinary Medicine. "Now I don't have to spend time developing assays for
these hormones."
Specializing in animal welfare of domestic large animals, Stull has studied issues such as veal-calf management techniques, alternative methods of raising heifer calves, stress factors for growing hogs and long-distance transportation of horses.
"Industry is interested in stress and animal welfare both from an economic standpoint and in terms of public perception," she says. "Also, with agricultural trade becoming global, we have to make sure that our minimum standards are acceptable to our international trading partners."
Science's growing understanding of the biology of stress has equipped Stull to objectively investigate the tough issues in animal agriculture, including a 1992 study of veal production. Because male calves are of little value to dairy producers, they are commonly removed from their mothers at birth so that the cow's milk can be harvested. These bull calves are sold to veal production facilities and housed in individual, stall-like enclosures. They are fed a liquid milk-replacer diet for 16 to 20 weeks; then they are processed for their pale-colored tender meat.
Although that system for raising veal calves had raised charges of animal cruelty, Stull's study, which included measurement of stress indicators such as the hormone cortisol, found that most veal calves were well-fed and humanely cared for. However, because the calves usually were not allowed to consume the antibody-rich colostrum or "first milk" from their mothers, their young immune systems were quite weakened and they might be vulnerable to disease, especially if intermingled with others in groups.
Stull's major recommendation was that veal calves be given the protective colostrum shortly following birth.
While the confined management system for veal calves may not match up with the idyllic image of pasture-raised cows, there was no sign that the veal calves were suffering from abusive or stressful treatment, she concluded.
"It's very hard to raise a calf without colostrum, which suggests that existing veal management practices were actually very good," she says, noting that veal calves have only a 5 percent mortality rate, compared to a higher mortality rate for heifer calves.
"Stress can't entirely be avoided, so we need to develop appropriate management systems that minimize stress," he says.
With that goal in mind, scientists keep probing the biological mysteries of stress, trying to define and characterize it in quantifiable terms, hoping to understand what conditions stimulate a stress response in individual members of countless animal species.
"We need to know how each animal will respond to various stressors," says Joy Mench. "It's hard enough for me to know how another person might respond to a stress, much less to get inside an animal's mind. That's the big black box."
