Category: Steroids

DENVER–The asthma medications beclomethasone and theophylline have reported side effects, such memory, mood and behavior changes, but an article in the March issue of the journal Pediatrics shows that in most children, the drugs cause no major changes in behavior or reasoning skills. Both drugs have been prescribed to treat asthma for decades.

"For the most part, mainstream drugs used to treat asthma are safe-in this case safe from psychological consequences," said Bruce Bender, Ph.D., head of Neuropsychology at National Jewish Medical and Research Center and principal investigator of the study. "Patients with chronic illness in general tend not to take their medications. When a parent has doubts about a medication, that tendency is amplified, often to the child's detriment in the long run. We hope that this study will help alleviate some of the fears parents may have about giving a child beclomethasone or theophylline."

Parents of more than 100, 6- to 17-year-old children with asthma completed behavioral questionnaires at the beginning of the study, at one month and one year. The children, who all had been diagnosed with asthma on average for 7 years, were tested for attention, concentration, memory, problem solving and learning skills. No significant side effects or differences between beclomethasone and theophylline were found in the study.

Although theophylline has a reputation among doctors and parents for causing behavioral problems in children, this research shows this isn't true in the age group examined. "No one has really looked at the potential psychological side effects of inhaled steroids before," Bender said. "There have been a couple of case reports that stated children developed serious behavior problems on inhaled steroids, but these reports often aren't accurate."

The study found that neither beclomethasone nor theophylline should be avoided because of concern over significant psychological side effects. But there may be a subset of pre-school age children who do have behavioral changes while taking either of the drugs.

Theophylline continues to be prescribed to some people with severe asthma, although doctors have started moving away from its use in general.

"Possible psychological changes in response to asthma medications must be addressed," Bender said. "Careful discussion with the child and the parents may lead to a decision to try another medication. But in some cases, particularly where more serious changes in mood or behavior are noted, referral to a mental health professional may prove more effective."

A new study suggests that a substance made by immune cells plays a key role in the progression of a disease in animals that closely mimics multiple sclerosis (MS). The findings further suggest that blocking the molecule, known as macrophage migration inhibitory factor (MIF) might prevent the progression of the disease.

Researchers at The Ohio State University Medical Center conducted the study using mice that develop a disease that mimics MS. They compared these animals to similar mice that lacked MIF, an immune-system signaling molecule.

The results show that the animals without MIF develop the initial, acute phase of the disease, but then show no signs of further progression.

The study is published as a Cutting Edge paper in the November 1, 2005, issue of the Journal of Immunology.

“Our results suggest that MIF may be less important for initiating MS, but that it may be necessary for MS progression,” says principal investigator Caroline C. Whitacre, professor of molecular virology, immunology and medical genetics.

“These findings indicate that in the future we can perhaps use MIF levels to predict the onset of a relapse. But more importantly, perhaps this study will lead to drugs that can halt the course of MS by blocking the action of MIF.”

MS is an inflammatory, autoimmune disease which primarily affects the brain and spinal cord. Autoimmune diseases occur when the body's own immune cells destroy tissues in the body. In MS, immune cells destroy the myelin sheath that surrounds nerve fibers in the brain and spinal cord. Myelin is a fatty substance that insulates nerve fibers and enables them to transmit impulses.

According to the National MS Society, about 400,000 Americans are living with MS and about 10,400 new cases are diagnosed yearly. The disease usually strikes between the ages of 20 and 40, and it is more common in women. MS symptoms vary from person to person. Some individuals experience unusual fatigue, numbness and tingling; others can have loss of balance and difficulty walking; still others develop slurred speech, double vision, tremors or bladder problems.

In about 85 percent of cases, MS shows a pattern of remission and relapse, with no warning as to when a relapse will occur.

For this study, Whitacre and a group of colleagues used mice that develop the MS-like condition known as experimental autoimmune encephalomyelitis (EAE). The mice develop the disease after being inoculated with a myelin protein. The researchers compared these mice to mice that were identical except that they lacked the gene for MIF.

After inoculation, the mice with the MIF gene showed progressive EAE. In contrast, the mice lacking the MIF gene showed signs of early disease, but after about 20 days, these mice recovered and showed no further sign of progression.

Along with Whitacre, Abhay R. Satoskar, assistant professor of microbiology; Nicole D. Powell, Tracey L. Papenfuss, Melanie A. McClain, Ingrid E. Gienapp, Todd M. Shawler, all of the Department of Molecular Virology, Immunology, and Medical Genetics, worked on the research.

The study also gave the investigators insights into the mechanism by which MIF influences the course of disease. They found that MIF blocked the steroid hormone, corticosterone (known as cortisol, in humans). Animals missing MIF had high levels of the steroid, while those with MIF showed very low levels.

The level of the steroid hormone, in turn, caused important immune-system changes in the animals that are likely to affect the disease.

For example, the mice with MIF (and low levels of the steroid hormone) showed high levels of immune-system cytokines or products that promote inflammation. Mice that lacked MIF (and had high levels of the steroid), on the other hand, showed high levels of immune-system cytokines or products that suppress inflammation .

“Our evidence overall suggests that the inhibition of this steroid hormone by MIF has an important influence on the immune system and in determining whether the disease progresses or not,” Whitacre says.

Funding from the National Institute of Allergy and Infectious Diseases supported this research.

NewsPsychology (June 6, 2012) — An Indiana University biologist has shown that natural variation in measures of the brain’s ability to process steroid hormones predicts functional variation in aggressive behavior.

The new work led by Kimberly A. Rosvall, a postdoctoral fellow and assistant research scientist in the IU Bloomington College of Arts and Sciences’ Department of Biology, has found strong and significant relationships between aggressive behavior in free-living birds and the abundance of messenger RNA in behaviorally relevant brain areas for three major sex steroid processing molecules: androgen receptor, estrogen receptor and aromatase.

“Individual variation is the raw material of evolution, and in this study we report that free-living birds vary in aggression and that more aggressive individuals express higher levels of genes related to testosterone processing in the brain,” she said. “We’ve long hypothesized that the brain’s ability to process steroids may account for individual differences in hormone-mediated behaviors, but direct demonstrations are rare, particularly in unmanipulated or free-living animals.”

Rosvall said the study shows that aggression is strongly predicted by individual variation in gene expression of the molecules that initiate the genomic effects of testosterone. The new work, “Neural sensitivity to sex steroids predicts individual differences in aggression: implications for behavioral evolution,” was published June 6 in Proceedings of The Royal Society B.

The findings are among the first to show that individual variation in neural gene expression for three major sex steroid processing molecules predicts individual variation in aggressiveness in both sexes in nature, results that should have broad implications for understanding the mechanisms by which aggressive behavior may evolve.

“On the one hand, we have lots of evidence to suggest that testosterone is important in the evolution of all kinds of traits,” Rosvall noted. “On the other hand, we know that individual variation is a requirement for natural selection, but individual variation in testosterone does not always predict behavior. This conundrum has led to debate among researchers about how hormone-mediated traits evolve.”

To find such strong relationships between behavior and individual variation in the expression of genes related to hormone-processing is exciting because it tells scientists that evolution could shape behavior via changes in the expression of these genes, as well as via changes in testosterone levels themselves.

The team measured natural variation in aggressiveness toward the same sexes in male and female free-living dark-eyed juncos (Junco hyemalis) early in the breeding season. The dark-eyed junco is a North American sparrow that is well studied with respect to hormones, behavior and sex differences. By comparing individual differences in aggressiveness (flyovers or songs directed at intruders) to circulating levels of testosterone and to neural gene expression for the three major sex steroid processing molecules, the researchers were able to quantify measures of sensitivity to testosterone in socially relevant brain areas: the hypothalamus, the ventromedial telencephalon and the right posterior telencephalon.

Their results suggest selection could shape the evolution of aggression through changes in the expression of androgen receptor, estrogen receptor and aromatase in both males and females, to some degree independently of circulating levels of testosterone. They found, for example, that males that sing more songs at an intruder have more mRNA for aromatase and estrogen receptor in the posterior telencephalon, and also that males and females that dive-bomb an intruder more frequently have more androgen receptor, estrogen receptor and aromatase mRNA in brain tissues including the medial amygdala, an area of the brain that’s known to control aggression in rodents and other birds. mRNA are single-stranded copies of genes that are translated into protein molecules.

The work reveals there is ample variation in hormone signal and in gene expression on which selection may act to affect aggressiveness. It also establishes a prerequisite for the evolution of testosterone-mediated characteristics through changes in localized gene expression for the key molecules that process sex steroids, and suggests that trait evolution can occur with some degree of independence from circulating testosterone levels.

“Researchers have thought this was probably the case for about a hundred years, based on a lot of really important work that uses experimental manipulations like castration or hormone replacement,” Rosvall said. “But very few people have looked to see if individuals actually do vary in expression of these genes, and whether this individual variation means anything, in terms of an animal’s behavior. Our work shows that it does.”

The new insights into how neuroendocrine mechanisms of aggression may be modified as populations diverge into species also offer opportunities for future research, including trying to determine whether genes that are up- or down-regulated in response to environmental stimuli may be the same genes that contribute to the evolution of certain traits and characteristics.

Co-authors on the paper with Rosvall were biology Ph.D. candidate Christine M. Bergeon Burns, biology professor J.L. Goodson, Department of Psychological and Brain Sciences professor Dale Sengelaub, and Distinguished Professor of Biology and Gender Studies Ellen D. Ketterson, all of Indiana University; and Ph.D. candidate Julia Barske and professor Barney A. Schlinger of University of California Los Angeles. The work was funded by the National Institutes of Health, the Indiana Academy of Sciences and the National Science Foundation.

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Story Source:

The above story is reprinted from materials provided by Indiana University, via Newswise.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Journal Reference:

1. K. A. Rosvall, C. M. Bergeon Burns, J. Barske, J. L. Goodson, B. A. Schlinger, D. R. Sengelaub, and E. D. Ketterson. Neural sensitivity to sex steroids predicts individual differences in aggression: implications for behavioural evolution. Proc. R. Soc. B, June 6, 2012 DOI: 10.1098/rspb.2012.0442

AMHERST, Mass. — Athletes taking the controversial performance enhancer known as "andro" may be affecting their moods as well as their muscles, suggests a study published by University of Massachusetts researchers in the July issue of the journal Endocrinology. The study was conducted by doctoral students Constanza Villalba and Catherine Auger under the direction of professor Geert de Vries. Auger is now a postdoctoral researcher at Johns Hopkins University. Although the study was conducted on rats, the implications for humans are important, according to the scientists.

"Andro," or androstenedione, is a steroid; a hormone that is produced in the body by males and females. It is sometimes sold as an over-the-counter nutritional supplement. Andro garnered attention last year when St. Louis Cardinals star hitter Mark McGwire acknowledged using it to help him train. Since then, scientists, doctors, and ethicists have been working to understand the effects of andro on the body. But while many researchers have been concentrating on how andro affects muscles and athletic performance, the UMass group of scientists has focused on what andro does to the brain. The study was conducted through the University's Center for Neuroendocrine Studies, the Neuroscience and Behavior Program, and the department of psychology.

"Steroids like andro and its more potent counterpart, testosterone, affect more than just muscle mass and home-run ability," said Villalba. "They can also affect the brain by changing the levels of neurotransmitters and consequently stimulating libido and aggression." Steroids, she explains, are critically important hormones produced in the body, in both males and females. While steroids are responsible for puberty, they also have a role in growth, behaviors, and brain development.

"Humans taking andro could potentially be susceptible to steroid-induced rage, or increased aggression as a result of the extra source of hormone," said Villalba.

Specifically, researchers studied andro's effect on a neurotransmitter called vasopressin. Vasopressin plays several roles in the brain: it governs thirst, wake-sleep cycles, and "the focus of the research" aggression. The scientists determined that, like testosterone, andro enables males to maintain high levels of vasopressin. This held true even in rats that lacked the ability to make their own male hormones.

 Glucocorticoids — a type of steroid hormone — are widely used in a number of medical disorders. Worldwide, it is estimated that almost 5% of postmenopausal women take glucocorticoids. As well as having specific benefits, Glucocorticoids have side effects. One of the potentially most important is that glucocorticoid use is associated with bone loss, which is most rapid in the first 3-6 months of treatment, potentially leading to serious complications and osteoporosis in many postmenopausal women.

The International Osteoporosis Foundation, along with the European Society for Calcified Tissue, launched new guidance on glucocorticoid use at the European Congress on Osteoporosis and Osteoarthritis (which took place in Bordeaux from March 21 — 24, 2012). Given the special relevance to postmenopausal women, the International Menopause Society (IMS) is supporting the publication of the guidance.

Dr Tobie de Villiers, President of the International Menopause Society (IMS), commented, "Bone loss is a concern for all women around the age of menopause, and especially for the almost 5% of postmenopausal women worldwide who take oral glucocorticoid therapy. The IMS encourages women to be aware of this potentially dangerous side-effect of therapy and to discuss what precautions can be taken with their doctors."

Continuing, Dr de Villiers said "The ovaries stop producing estrogen around the time of the menopause, meaning that women find that the risk of bone loss and osteoporosis increases. This is already difficult for many women to cope with, so we need to be especially careful that the medicines which women take for other conditions don't actually harm women's bones. Glucocorticoids are important and valuable medicines, but like all medicines they have side effects and their use must be customised and monitored. Women, especially women after their menopause, need to be more aware of the possibility of this serious side-effect. These guidelines are aimed at allowing national organisations to develop effective systems to use glucocorticoids effectively."

A person who drinks too much alcohol may be able to perform complicated tasks, such as dancing, carrying on a conversation or even driving a car, but later have no memory of those escapades. These periods of amnesia, commonly known as "blackouts," can last from a few minutes to several hours.

Now, at Washington University School of Medicine in St. Louis, neuroscientists have identified the brain cells involved in blackouts and the molecular mechanism that appears to underlie them. They report July 6, 2011, in The Journal of Neuroscience, that exposure to large amounts of alcohol does not necessarily kill brain cells as once was thought. Rather, alcohol interferes with key receptors in the brain, which in turn manufacture steroids that inhibit long-term potentiation (LTP), a process that strengthens the connections between neurons and is crucial to learning and memory.

Better understanding of what occurs when memory formation is inhibited by alcohol exposure could lead to strategies to improve memory.

"The mechanism involves NMDA receptors that transmit glutamate, which carries signals between neurons," says Yukitoshi Izumi, MD, PhD, research professor of psychiatry at Washington University School of Medicine in St. Louis. "An NMDA receptor is like a double-edged sword because too much activity and too little can be toxic. We've found that exposure to alcohol inhibits some receptors and later activates others, causing neurons to manufacture steroids that inhibit LTP and memory formation."

Izumi says the various receptors involved in the cascade interfere with synaptic plasticity in the brain's hippocampus, which is known to be important in cognitive function. Just as plastic bends and can be molded into different shapes, synaptic plasticity is a term scientists use to describe the changeable properties of synapses, the sites where nerve cells connect and communicate. LTP is the synaptic mechanism that underlies memory formation.

The brain cells affected by alcohol are found in the hippocampus and other brain structures involved in advanced cognitive functions. Izumi and first author Kazuhiro Tokuda, MD, research instructor of psychiatry, studied slices of the hippocampus from the rat brain.

When they treated hippocampal cells with moderate amounts of alcohol, LTP was unaffected, but exposing the cells to large amounts of alcohol inhibited the memory formation mechanism.

"It takes a lot of alcohol to block LTP and memory," says senior investigator Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry. "But the mechanism isn't straightforward. The alcohol triggers these receptors to behave in seemingly contradictory ways, and that's what actually blocks the neural signals that create memories. It also may explain why individuals who get highly intoxicated don't remember what they did the night before."

But not all NMDA receptors are blocked by alcohol. Instead, their activity is cut roughly in half.

"The exposure to alcohol blocks some NMDA receptors and activates others, which then trigger the neuron to manufacture these steroids," Zorumski says.

The scientists point out that alcohol isn't causing blackouts by killing neurons. Instead, the steroids interfere with synaptic plasticity to impair LTP and memory formation.

"Alcohol isn't damaging the cells in any way that we can detect," Zorumski says. "As a matter of fact, even at the high levels we used here, we don't see any changes in how the brain cells communicate. You still process information. You're not anesthetized. You haven't passed out. But you're not forming new memories."

Stress on the hippocampal cells also can block memory formation. So can consumption of other drugs. When combined, alcohol and certain other drugs are much more likely to cause blackouts than either substance alone.

The researchers found that if they could block the manufacture of steroids by neurons, they also could preserve LTP in the rat hippocampus. And they did that with drugs called 5-alpha-reductase inhibitors. These include finasteride and dutasteride, which are commonly prescribed to reduce a man's enlarged prostate gland. In the brain, however, those substances seem to preserve memory.

"We would expect there may be some differences in the effects of alcohol on patients taking these drugs," Izumi says. "Perhaps men taking the drugs would be less likely to experience intoxication blackouts."

The researchers plan to study 5-alpha-reductase inhibitors to see how easily they get into the brain and to determine whether those drugs, or similar substances, might someday play a role in preserving memory.

This work was supported by grants from the National Institute of Mental Health, the National Institute of General Medical Sciences, and the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH), and by the Bantley Foundation.

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Journal Reference:

1. Tokuda K, Izumi Y, Zorumski CF. Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation. The Journal of Neuroscience, Vol. 31(27), pp. 9905-9909. July 6, 2011

 A multicenter pilot study of etanercept for treatment of dermatomyositis found no major safety concerns and many patients treated with the drug were successfully weaned from steroid therapy. These results are encouraging, but larger studies are needed to further investigate the safety and efficacy of etanercept. Results of this clinical trial are available in Annals of Neurology, a journal published by Wiley-Blackwell on behalf of the American Neurological Association.

Dermatomyositis is a type of inflammatory myopathy that causes inflammation and progressive weakness in muscles, and is often accompanied by a purple or red skin rash. In some patients the standard treatment for dermatomyositis is prednisone, but despite steroid therapy many patients continue to experience disabling weakness and have the added unpleasant side affects associated with the steroids. Prior studies suggest that tumor necrosis factor (TNF) may play a role in the development of dermatomyositis. TNF — a type of protein molecule involved in systemic inflammation — is associated with other inflammatory diseases including rheumatoid arthritis, ankylosing spondylitits, and psoriatic arthritis, all of which seem to be responsive to etanercept therapy in studies.

"Given the positive response of other inflammatory diseases to etanercept, our pilot study aimed to assess the safety and tolerability of this drug in dermatomyositis, along with the feasibility of a forced prednisone taper," said Anthony Amato, MD, with the Department of Neurology at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. Researchers conducted a double-blind, placebo-controlled trial of etanercept (50 mg weekly) in16 patients with dermatomyositis. The year-long trial randomized 11 participants to etanercept and 5 to placebo, with subjects tapered off prednisone in a standardized schedule over the first 24 weeks of the study.

Trial results revealed no significant increase in adverse event rates in the treatment group compared to placebo. Of the 11 subjects treated with etanercept, 5 were successfully tapered from steroid therapy, with a median time to treatment failure (inability to wean off prednisone on schedule) in this group of 358 days. All placebo subjects were treatment failures with a median of 148 days to failure of treatment. Researchers reported that 5 etanercept-treated participants and 1 placebo-treated participant developed a worsening rash. After week 24 the median of the average prednisone dosage was 29.2 mg/day in the placebo group and 1.2 mg/day in the etanercept cohort.

Additionally, two etanercept-treated participants developed elevated anti-nuclear antibodies during the study, but none developed systemic lupus erythematosus. The authors noted that the small sample size and allowance of rescue treatment in this trial limit conclusions of etanercept efficacy to those related to steroid-sparing. "Etanercept was safe and well-tolerated in participants in our one-year study," concluded Dr. Amato. "Further study of the safety and efficacy of etanercept as a dermatomyositis treatment is warranted."

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Journal Reference:

1. Anthony A. Amato. A randomized, pilot trial of etanercept in dermatomyositis the muscle study group. Annals of Neurology, 2011; DOI: 10.1002/ana.22477