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LESS STRESS ON CORTISOL
HMS researchers gain new understanding of common hormone.
Louis Muglia and Joseph Majzoub are helping to clarify the role played by glucocorticoids in fetal and adult life.
Perched atop the kidneys, on either side of the body, lie two pyramid-shaped lumps known as the adrenal glands. Puny in comparison with the mountainous kidneys below, these two glands become transformed-during moments of stress-into tiny powerhouses of physiological activity, producing and dispatching hormonal messengers.
For years, endocrinologists have deemed the adrenals and the "stress hormones" they produce to be absolutely essential for survival. Now, Harvard Medical School researchers at Children's Hospital have made a discovery that challenges a central aspect of this dogma.
In the Feb. 2 issue of Nature, they report that mutant mice lacking one of the primary adrenal hormones, the glucocorticoids, are not only able to survive but also reproduce. However, the hormone does appear critical for prenatal development. The mutants, when born to mice that do not produce glucocorticoids, die soon after birth because their lungs have failed to develop.
"The long-standing belief that you need intact adrenal function to withstand stress [postnatally] is probably not entirely true," said Louis Muglia, instructor in pediatrics, and lead author of the study. "You need glucocorticoids to get lungs to develop fetally, but the adult mutant mice have virtually no glucocorticoids and they adapt fine."
The researchers-while suggesting that glucocorticoids play their most critical role during fetal development-are not saying that these hormones serve no function in adults. "My hypothesis-which is just that now-is that glucocorticoids probably operate for the most part as a regulator of fuel metabolism in a postnatal state," said Joseph Majzoub, associate professor of pediatrics and medicine.
This hypothesis, if correct, could lead to new approaches for treating anorexia nervosa, depression and the chronic wasting away that accompanies AIDS. Their ongoing work is helping shed light on a pathway critical to appetite suppression, and helping to better understand how that pathway is modulated by glucocorticoids.
Majzoub began to question the role played by the glucocorticoids as a result of a puzzling clinical observation. As an endocrinologist, he observed many patients who were unable to produce cortisol (a form of glucocorticoid). In some cases, the deficiency was due to the fact that the patients had a lack of adrenal gland function. This syndrome-known as Addison's disease-is fatal unless patients are treated with cortisol.
The lungs of normal mice (left) exhibit prominent air spaces compared to those of CRH-deficient mice (center). Giving glucocorticoids to pregnant CRH-deficient females results in normal lung development in offspring(right).
However, in other patients-mostly children suffering from brain tumors-the lack of cortisol was the result of damage to the hypothalamus, which produces corticotropin- releasing hormone (CRH), a stimulator of cortisol. Because cortisol is known to stunt growth, these children were not given the hormone-and yet they did just fine.
"I said, 'Gee, this doesn't sound right.' I thought cortisol was important for life and I thought you would die without it," recounted Majzoub.
He began to think that these children, ironically, might be getting along without the cortisol because they were also missing CRH. In other words, the entire CRH- cortisol pathway had been shut down, and that apparently was less traumatic than having an absence of cortisol alone.
CRH, which was discovered in 1981, is still something of a mystery to endocrinologists. It is known to stimulate the production of corticotropin (ACTH) in the pituitary, which in turn stimulates the production of cortisol by the adrenals. In addition, CRH is thought to suppress a number of vital activities, such as growth, libido and appetite.
"It's easy to identify someone with high levels of CRH. They're very fatigued, they lose weight, and they turn off many sexual functions-testicular and ovarian function," Muglia explained. These are precisely the symptoms of people suffering from Addison's disease-who, it turns out, have high levels of CRH in their blood.
These high levels of CRH are, in fact, due to the lack of cortisol in these patients. Cortisol, which is known to turn fat and muscle into glucose during times of extreme stress, also turns off CRH production in the hypothalamus. (See diagram on page 3.)
Thus, because Addison's patients lack adrenal glands for manufacturing cortisol, the CRH machinery is not appropriately regulated. The hypothalamus gets stuck in high gear, churning out too much CRH.
"I thought maybe we all had it wrong, and, in fact, it's not the cortisol lack but the high CRH that is killing these patients," Majzoub said.
To test this idea-and more generally to see what CRH and glucocorticoids were actually doing-he and his colleagues took advantage of techniques for knocking out genes. By selectively mutating an individual gene, they created a breed of mice with no CRH and hence no glucocorticoids.
"A lot of people said, 'You're nuts-these animals aren't going to survive,'" said Majzoub. But they did survive-and with almost no detectable difference from their normal counterparts. Even the researchers were surprised. They expected the mice might either be overweight, due to the lack of CRH, which normally suppresses appetite, or underweight, due to the lack of glucocorticoids, which help fuel the body.
An even bigger surprise came when the researchers tried breeding the knockout mice . . . and succeeded. "I wasn't sure whether-because CRH is made in the gonads-they were going to be fertile or not. As it turns out, glucocorticoids did not seem to be essential for maturation of germ cells in either sex," Muglia said.
But the hormone did seem to be essential for the maturation of the fetus. The fetal offspring of mice missing the functional gene for CRH died within 12 hours of being born because of severe lung impairment. The researchers were puzzled at first. Genetically the newborns were no different from their knockout parents-both carried the same mutant CRH gene. The crucial difference was that the knockout mothers had themselves been born to glucocorticoid-producing mice.
This strongly suggested that glucocorticoids are essential for the developing fetus. And, in fact, women in premature labor are often given glucocorticoids to accelerate maturation of the fetal lungs, although it has never been clear exactly how these hormones help the lungs develop.
The researchers then tried rescuing the fetal mice. They began feeding glucocorticoid-spiked water to a new generation of pregnant knockout moms halfway through pregnancy and two weeks after birth. "When we gave the moms glucocorticoids, all the fetuses were happy as could be," said Muglia. "Their lungs were perfectly normal." (See illustration.)
This finding helped answer a puzzling clinical observation: Children born with little adrenal function, and hence low levels of cortisol, have normal lung development. As with the mice, it appears that the mothers can provide their fetuses with the vital hormone.
As it turns out, the glucocorticoids also probably play an equally crucial role in motherhood after pregnancy. In a final twist, the researchers mated knockout females and normal males to see what would happen if a heterozygous (glucocorticoid-producing) fetus was raised by a homozygous (glucocorticoid-deficient) mother. The mice were born on time. And, unlike their homozygous counterparts, they did not die within 12 hours.
The CRH-producing hypothalamus and the cortisol-producing adrenal glands are connected by a negative feedback loop. Cortisol acts as a brake on the production of CRH.
However, these apparently healthy mice began wasting away after the first week of life. "And the reason was the moms didn't produce milk. It turns out glucocorticoids are necessary for milk production," said Muglia.
These findings by Majzoub, Muglia, and their co-workers have obvious potential implications for clinical treatment of patients with damage to the hypothalamus. Said Majzoub: "Cortisol is not as important as everyone thought for treating these patients." Their findings could also be used to develop treatments for patients suffering from anorexia nervosa and depression. These patients are known to have high levels of CRH in their cerebrospinal fluid. Blocking CRH, which appears to suppress appetite, might help these patients retain a desire to eat. For a similar reason, a CRH-blocker might be able to slow the chronic wasting seen in AIDS patients.
"This work points to a better understanding of the true role of glucocorticoids, which are among the most powerful and commonly prescribed drugs," said Majzoub.
--Misia Landau
HMS researchers gain new understanding of common hormone.
Louis Muglia and Joseph Majzoub are helping to clarify the role played by glucocorticoids in fetal and adult life.
Perched atop the kidneys, on either side of the body, lie two pyramid-shaped lumps known as the adrenal glands. Puny in comparison with the mountainous kidneys below, these two glands become transformed-during moments of stress-into tiny powerhouses of physiological activity, producing and dispatching hormonal messengers.
For years, endocrinologists have deemed the adrenals and the "stress hormones" they produce to be absolutely essential for survival. Now, Harvard Medical School researchers at Children's Hospital have made a discovery that challenges a central aspect of this dogma.
In the Feb. 2 issue of Nature, they report that mutant mice lacking one of the primary adrenal hormones, the glucocorticoids, are not only able to survive but also reproduce. However, the hormone does appear critical for prenatal development. The mutants, when born to mice that do not produce glucocorticoids, die soon after birth because their lungs have failed to develop.
"The long-standing belief that you need intact adrenal function to withstand stress [postnatally] is probably not entirely true," said Louis Muglia, instructor in pediatrics, and lead author of the study. "You need glucocorticoids to get lungs to develop fetally, but the adult mutant mice have virtually no glucocorticoids and they adapt fine."
The researchers-while suggesting that glucocorticoids play their most critical role during fetal development-are not saying that these hormones serve no function in adults. "My hypothesis-which is just that now-is that glucocorticoids probably operate for the most part as a regulator of fuel metabolism in a postnatal state," said Joseph Majzoub, associate professor of pediatrics and medicine.
This hypothesis, if correct, could lead to new approaches for treating anorexia nervosa, depression and the chronic wasting away that accompanies AIDS. Their ongoing work is helping shed light on a pathway critical to appetite suppression, and helping to better understand how that pathway is modulated by glucocorticoids.
Majzoub began to question the role played by the glucocorticoids as a result of a puzzling clinical observation. As an endocrinologist, he observed many patients who were unable to produce cortisol (a form of glucocorticoid). In some cases, the deficiency was due to the fact that the patients had a lack of adrenal gland function. This syndrome-known as Addison's disease-is fatal unless patients are treated with cortisol.
The lungs of normal mice (left) exhibit prominent air spaces compared to those of CRH-deficient mice (center). Giving glucocorticoids to pregnant CRH-deficient females results in normal lung development in offspring(right).
However, in other patients-mostly children suffering from brain tumors-the lack of cortisol was the result of damage to the hypothalamus, which produces corticotropin- releasing hormone (CRH), a stimulator of cortisol. Because cortisol is known to stunt growth, these children were not given the hormone-and yet they did just fine.
"I said, 'Gee, this doesn't sound right.' I thought cortisol was important for life and I thought you would die without it," recounted Majzoub.
He began to think that these children, ironically, might be getting along without the cortisol because they were also missing CRH. In other words, the entire CRH- cortisol pathway had been shut down, and that apparently was less traumatic than having an absence of cortisol alone.
CRH, which was discovered in 1981, is still something of a mystery to endocrinologists. It is known to stimulate the production of corticotropin (ACTH) in the pituitary, which in turn stimulates the production of cortisol by the adrenals. In addition, CRH is thought to suppress a number of vital activities, such as growth, libido and appetite.
"It's easy to identify someone with high levels of CRH. They're very fatigued, they lose weight, and they turn off many sexual functions-testicular and ovarian function," Muglia explained. These are precisely the symptoms of people suffering from Addison's disease-who, it turns out, have high levels of CRH in their blood.
These high levels of CRH are, in fact, due to the lack of cortisol in these patients. Cortisol, which is known to turn fat and muscle into glucose during times of extreme stress, also turns off CRH production in the hypothalamus. (See diagram on page 3.)
Thus, because Addison's patients lack adrenal glands for manufacturing cortisol, the CRH machinery is not appropriately regulated. The hypothalamus gets stuck in high gear, churning out too much CRH.
"I thought maybe we all had it wrong, and, in fact, it's not the cortisol lack but the high CRH that is killing these patients," Majzoub said.
To test this idea-and more generally to see what CRH and glucocorticoids were actually doing-he and his colleagues took advantage of techniques for knocking out genes. By selectively mutating an individual gene, they created a breed of mice with no CRH and hence no glucocorticoids.
"A lot of people said, 'You're nuts-these animals aren't going to survive,'" said Majzoub. But they did survive-and with almost no detectable difference from their normal counterparts. Even the researchers were surprised. They expected the mice might either be overweight, due to the lack of CRH, which normally suppresses appetite, or underweight, due to the lack of glucocorticoids, which help fuel the body.
An even bigger surprise came when the researchers tried breeding the knockout mice . . . and succeeded. "I wasn't sure whether-because CRH is made in the gonads-they were going to be fertile or not. As it turns out, glucocorticoids did not seem to be essential for maturation of germ cells in either sex," Muglia said.
But the hormone did seem to be essential for the maturation of the fetus. The fetal offspring of mice missing the functional gene for CRH died within 12 hours of being born because of severe lung impairment. The researchers were puzzled at first. Genetically the newborns were no different from their knockout parents-both carried the same mutant CRH gene. The crucial difference was that the knockout mothers had themselves been born to glucocorticoid-producing mice.
This strongly suggested that glucocorticoids are essential for the developing fetus. And, in fact, women in premature labor are often given glucocorticoids to accelerate maturation of the fetal lungs, although it has never been clear exactly how these hormones help the lungs develop.
The researchers then tried rescuing the fetal mice. They began feeding glucocorticoid-spiked water to a new generation of pregnant knockout moms halfway through pregnancy and two weeks after birth. "When we gave the moms glucocorticoids, all the fetuses were happy as could be," said Muglia. "Their lungs were perfectly normal." (See illustration.)
This finding helped answer a puzzling clinical observation: Children born with little adrenal function, and hence low levels of cortisol, have normal lung development. As with the mice, it appears that the mothers can provide their fetuses with the vital hormone.
As it turns out, the glucocorticoids also probably play an equally crucial role in motherhood after pregnancy. In a final twist, the researchers mated knockout females and normal males to see what would happen if a heterozygous (glucocorticoid-producing) fetus was raised by a homozygous (glucocorticoid-deficient) mother. The mice were born on time. And, unlike their homozygous counterparts, they did not die within 12 hours.
The CRH-producing hypothalamus and the cortisol-producing adrenal glands are connected by a negative feedback loop. Cortisol acts as a brake on the production of CRH.
However, these apparently healthy mice began wasting away after the first week of life. "And the reason was the moms didn't produce milk. It turns out glucocorticoids are necessary for milk production," said Muglia.
These findings by Majzoub, Muglia, and their co-workers have obvious potential implications for clinical treatment of patients with damage to the hypothalamus. Said Majzoub: "Cortisol is not as important as everyone thought for treating these patients." Their findings could also be used to develop treatments for patients suffering from anorexia nervosa and depression. These patients are known to have high levels of CRH in their cerebrospinal fluid. Blocking CRH, which appears to suppress appetite, might help these patients retain a desire to eat. For a similar reason, a CRH-blocker might be able to slow the chronic wasting seen in AIDS patients.
"This work points to a better understanding of the true role of glucocorticoids, which are among the most powerful and commonly prescribed drugs," said Majzoub.
--Misia Landau
