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Testosterone Testing - Immunoassays Faulty in Women and Children

From Clinical Laboratory News:

Are there times when a test is so unreliable and imprecise that it simply shouldn’t be used with certain patients? That’s the debate swirling around total testosterone assays—direct immunoassays in particular—when used for testing in women and children. Concentrations of this steroid hormone may be as low as 0.17 nmol/L (5 ng/dL) for these populations, compared with 11.1 nmol/L (320 ng/dL), the lower range of normal in men. A growing body of evidence has clearly demonstrated that the performance of some immunoassays at such low concentrations is sub-par at best, prompting experts to question their use in women and children. Earlier this year, a consortium of professional associations and government agencies examined the issue and is now calling for long overdue testosterone assay standardization, an initiative that has major implications for manufacturers, labs, and public health.

William Rosner, MD, who co-chaired the consensus conference, has been a vocal advocate for improving the assays. “This [standardization effort] has implications for individual patients and for researchers. There’s a push on to treat women with testosterone, but we can’t know how much to give them or whether to give them any if we don’t have a way to accurately measure testosterone levels,” he said “At the same time, researchers can’t compare their results to anyone else’s, and they can’t compare their own results to results they obtained 10 years ago if they changed the method they’re using to measure testosterone.” Rosner is a professor of medicine at Columbia University in New York City.

The consensus effort, spearheaded by The Endocrine Society and Centers for Disease Control and Prevention (CDC) and endorsed by AACC, is encouraging the expert scientific and medical communities, third-party payers, manufacturers, funding entities, journals, and other stakeholders to undertake specific efforts to aid in improving the accuracy of testosterone measurements. The group’s consensus statement has been submitted for publication in The Journal of Clinical Endocrinology & Metabolism.

Issues about the performance of testosterone assays have risen to the fore as more potential applications for the analyte have become apparent. Testosterone levels once were primarily used in the work-up of men suspected of hypogonadism and in gender assignment for newborns with ambiguous genitalia.

More recently, research—not all of it concordant—has suggested testosterone may have a protective benefit in osteoporosis, type 2 diabetes, cardiovascular disease, obesity, and depression in men. Androgen replacement therapy in women also has gained favor as a means of boosting libido, bone density, and muscle mass. In addition, there has been growing recognition of and better treatments for polycystic ovary disease, a disease of androgen excess and the most common hormonal disorder in women of reproductive age. Meanwhile, the epidemic of obesity in children has been associated with precocious puberty, thereby increasing the need to determine androgen status in these patients. All of these factors have pumped up the volume of testing, particularly in women and children, who had not been part of the traditional testing population.

Rosner believes a big tent will be needed to achieve standardization of total testosterone assays because a complicated web of factors has contributed to their shortcomings. Medical journals, laboratories, regulators, lab testing and accrediting bodies, diagnostic manufacturers, and even payers all have had a hand in promulgating and perpetuating a lackluster assay, he contends.

Conventional radioimmunoassays (RIA) for measuring testosterone were developed in the early 1970s. These assays, which involve denaturing steroid-binding proteins to release testosterone followed by purification steps that remove numerous potentially interfering metabolites, are highly reliable when properly validated, according to experts. But they are cumbersome, time-consuming, costly, and, like other antibody assays, can have cross-reactivity issues.

As time went on, direct chemiluminescent, enzymatic, and fluorescent immunoassays came on the scene and surpassed conventional RIAs in use. These direct immunoassays provide rapid and inexpensive results, but they have several serious drawbacks as well. Due to lack of specificity of the antibodies, they tend to overestimate testosterone measurements. They also are prone to matrix effects and have inadequate sensitivity to measure low levels of testosterone accurately and reliably.

Perhaps because the direct immunoassays are acceptable in evaluating testosterone levels in most men, it was an easy leap to assume they would work well in women and children, too.

Notable strides towards standardization have been taken by the CDC since 2007. Among other things, the Division of Laboratory Sciences (DLS) has developed an accurate and precise reference method. The method uses a reference material from the Australian National Measurement Institute, the only one that’s currently available for testosterone, according to Hubert Vesper, PhD, chief of the protein biomarkers laboratory in CDC’s DLS. The National Institute of Standards and Technology (NIST) also has developed a serum-based product, which is considered a secondary reference material.

CDC took another important step earlier this year when it launched a standardization program for testosterone. The program is open to manufacturers, commercial and reference labs and involves fresh-frozen, single-donor serum samples with reference values.

CAP also has stepped up to the plate by offering, starting earlier this year, a separate accuracy-based proficiency testing program for steroid hormones, including testosterone. “It’s voluntary and at present is not required for CLIA certification,” said John Eckfeldt, MD, PhD, Ellis Benson professor and vice chair for clinical affairs in the department of laboratory medicine and pathology at the University of Minnesota in Minneapolis. “Labs that are concerned about accuracy and want to pay the extra money and take the extra time to participate will do so.”

As crucial as these efforts are, greater participation by manufacturers will be needed for testosterone immunoassays to leap forward in accuracy and precision at lower concentrations, according to experts.

Major reference labs have invested in and use mass spectrometry to measure testosterone, particularly for women and children.

Until mass spectrometry is a mainstream method, Fitzgerald urged labs relying on immunoassays to consider sending out any samples for measurement on women and children. “All the major reference labs have it available by mass spec, and as far as send-out tests go, it’s not extremely expensive. It’s on par with most send-out tests,” he observed. 

Posted: 7/29/2010 10:02:00 AM

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Bisphenol-A found in paper receipts

From The Washington Post:

As lawmakers and health experts wrestle over whether a controversial chemical, bisphenol-A, should be banned from food and beverage containers, a new analysis by an environmental group suggests Americans are being exposed to BPA through another, surprising route: paper receipts.

The Environmental Working Group found BPA on 40 percent of the receipts it collected from supermarkets, automated teller machines, gas stations and chain stores. In some cases, the total amount of BPA on the receipt was 1,000 times the amount found in the epoxy lining of a can of food, another controversial use of the chemical.

Sonya Lunder, a senior analyst with the environmental group, says BPA's prevalence on receipts could help explain why the chemical can be detected in the urine of an estimated 93 percent of Americans, according to the Centers for Disease Control and Prevention.

What remains unknown is how much of the chemical that may rub off onto the hands is absorbed through the skin or whether people then ingest BPA by handling food or touching their mouths.

Among those surveyed, receipts from Safeway supermarkets contained the highest concentration of BPA. A receipt taken from a store in the District contained 41 milligrams of the chemical. If the equivalent amount of BPA was ingested by a 155-pound adult, that would exceed EPA's decades-old safe exposure limit for BPA by 12 times.

The American Chemistry Council, which represents the chemical industry, said that while BPA can transfer from paper receipts to the skin, the level of absorption is low.

The Environmental Protection Agency, however, recognizing that paper coated in BPA may be a significant route of exposure, launched an effort this month to work with paper manufacturers, the chemical industry and environmental groups to encourage companies to find alternatives to BPA in receipts.

Appleton Papers, the nation's largest manufacturer of "thermal papers," the type often used for receipts, dropped BPA from its formulation in 2006 out of growing concerns about the safety of the chemical, said Kent Willetts, the company's vice president of strategic development. "We just realized we'd rather move away from it sooner than later," Willetts said.

Posted: 7/28/2010 9:06:00 AM

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Vitreous testing that could indicate diabetes or kidney failure

From the North County Times:

When autopsies and toxicology screens can't explain how a person died, toxicologists can turn to the fluid in a dead person's eye for answers.

Using new equipment and screening techniques, forensic toxicologists can perform tests that often are the only way to detect causes of death, such as diabetes or kidney disease, when no other cause is obvious.

The improved screening also could provide life-saving information for victims' families.

For example, a postmortem diagnoses of a hereditary disease such as diabetes might be a family's first warning that members are at risk.

Toxicologists began testing blood and fluid, or "vitreous," from the eye for abnormal chemical levels that could indicate diabetes or kidney failure.

Eventually, analysis could use the machines to measure insulin levels, detect thyroid disorders and determine how long someone had been suffering from untreated or inadequately treated diabetes.

Posted: 7/27/2010 4:24:00 PM

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Vitamin E–Rich Foods May Reduce Long-Term Risk for Dementia

From Medscape Today:

Vitamin E may play a modest role in altering the course of dementia, say researchers. Compared with participants with the lowest intake, investigators found that those patients with higher vitamin E intake were 25% less likely to develop dementia.

"When beta-amyloid — a hallmark of pathologic Alzheimer disease — accumulates in the brain, an inflammatory response is likely evoked that produces nitric oxide radicals and downstream neurodegenerative effects," report investigators led by Elizabeth Devore, ScD, from the Erasmus Medical Center in Rotterdam, the Netherlands. "Vitamin E is a powerful fat-soluble antioxidant that may help to inhibit the pathogenesis of dementia."

The results appear in the July issue of the Archives of Neurology and suggest that dietary antioxidants affect the early stages of dementia.

Vitamin E is found in whole-grain foods, eggs, milk, nuts, seeds, avocado, spinach, and unheated vegetable oils. The Rotterdam Study previously found that higher dietary intakes of vitamins E and C were associated with a lower risk for dementia and Alzheimer's disease.

In this new long-term follow-up of the Rotterdam Study, investigators followed participants for 9.6 years. The population-based prospective cohort study included 5395 people free of disease at baseline.

A total of 465 people developed dementia. Of these, 365 were diagnosed with Alzheimer's disease. The investigators found that higher dietary intake of vitamin E, but not vitamin C, beta carotene, or flavonoids, was associated with lower long-term risk for dementia.

These results conflict with previous findings, which suggested a link between vitamin C intake and dementia risk.

Dr. Maria Carrillo, PhD, senior director of medical and scientific relations at the Alzheimer's Association, acknowledged the finding is preliminary — it is still too early for specific recommendations on vitamin E intake, and excessive use can have negative cardiovascular effects, she said.

Posted: 7/23/2010 10:25:00 AM

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Cracking Down on Toxic Makeup

From TIME:

The Food and Drug Administration (FDA) may regulate foods and drugs relatively well—with some exceptions—but the agency can't require cosmetics companies to conduct safety assessments, control the labeling of products or force product recalls. Just a fifth of the chemicals in cosmetics have actually been assessed by the FDA's safety panel.

And the chemicals inside many cosmetics—shampoos, moiturizers, lipstick and more—are worth worrying about. Carcinogens like formaldehyde, neurotoxins like lead, endocrine disrupters like phthalates—they're often found, even in just trace amounts, in cosmetics and personal care items. An investigation by the Chicago Tribune in May found that some skin-whitening creams had dangerous levels of mercury, enough to cause kidney damage. Annie Leonard—the author of the book The Story of Stuff and its accompanying film—has made a short web video (The Story of Cosmetics) that tells the tale.

As Leonard points out, real change needs to come not just from the consumer, or even industry, but in the laws that govern cosmetic and chemical regulation. And there's some positive news from Washington: today Representatives Jan Schakowsky, Ed Markey and Tammy Baldwin introduced the Safe Cosmetics Act of 2010. The legislation aims to phase out cosmetic ingredients linked to cancer and developmental harm, improve protection for children and other vulnerable populations and close labeling loopholes that allow companies to classify any number of chemicals under innocuous terms like "fragrances."

Passing the bill won't easy—the Personal Care Products Council, a trade group for the industry, argues that the legislation would place impossible burdens on the FDA, and that it's "not based on credible and established scientific principles." But at the very least the industry does seem to recognize that it has a problem, and is open to strengthening regulation at the FDA level, which is a start.

Posted: 7/22/2010 11:45:00 AM

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Ampyra Runs Ahead of Other MS Treatments

From Minyanville:

Multiple sclerosis took center stage at the 2010 American Academy of Neurology annual conference in Toronto.

One of the biggest draws at the conference was new data from Acorda Therapeutics (ACOR) concerning its recently approved drug Ampyra. The drug was approved by the FDA on January 22 and is designed to help improve walking for patients with MS.

Ampyra is a new class of drug that isn’t made to slow the progression of MS like the other drugs on the market, but is meant to treat one of its most debilitating symptoms. MS is a degenerative disease caused by the deterioration of the protective coating of nerve cells that affects 400,000 people in the United States and 2.5 million people worldwide. As the nerves around the spinal cord and in the brain become damaged, patients often lose their ability to walk, move certain parts of their body, see properly, or control their attention span, as well as other incapacitating issues.

The data presented on Ampyra at AAN included an extension of two completed phase III studies that showed patients continued to improve their average baseline walking speed over the course of the 2.5-year period. The presentation at the conference also included data from one phase II trial and two phase III trials that showed 37.3% of patients who received Ampyra showed consistent improvement in their walking ability compared to 8.9% of patients who received placebo. The Ampyra-treated patients who responded to the therapy showed an average improvement in walking speed of 25.3%.

“Specialists with whom we spoke noted that patients were coming in requesting Ampyra, and the specialists had all started to write scripts,” wrote Leerink Swann analyst Josh Schimmer concerning his time at the conference. “On average they were in the process of starting roughly 1%-2% of their patients on therapy.”

Posted: 7/21/2010 2:03:00 PM

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FDA official leads charge against dangerous unapproved prescription drugs

From The Washington Post:

Tackling a serious and long-standing public health problem, Deborah Autor of the Food and Drug Administration (FDA) leads an ongoing, multi-year initiative to remove hundreds of potentially dangerous prescription medicines from the market that were never approved for their safety or effectiveness as required by law.

As director of the FDA's drug compliance office, Autor designed the program to identify the unapproved drugs, evaluated the public health consequences, explored the legal challenges, set up incentive, education and outreach programs, and initiated an aggressive enforcement effort.

The FDA so far has taken enforcement actions to remove more than 500 unapproved prescription drugs from the market, impacting more than 275 drug manufacturers and distributors. Autor estimates that unapproved medicines represent less than two percent of prescriptions filled every year. But in the multibillion-dollar U.S. prescription drug market, this means that many thousands of consumers are exposed to drugs that may be unsafe.

The targeted medications have included cough medicines, antihistamines, certain single-ingredient narcotics, analgesics for pain, anti-inflammatory drugs, migraine medicines, gastrointestinal pharmaceuticals and many other products, including some prescribed to children and some reportedly linked to deaths.

Many of these unapproved medications were on the market before Congress made successive changes to the drug approval process, including 1962 amendments that required that pharmaceuticals not only be safe but also effective. While most pre-1962 prescription remedies were later evaluated by the FDA, many claimed exemptions because they or similar drugs were marketed without FDA approval before the changes to the law.

Autor's team found that most of the "grandfathered" drugs had been changed their formulations, dosages, how they are administered, and for what patients and conditions they are recommended making them "new" drugs requiring formal review and approval. Other unapproved drugs were not even grandfathered, yet manufacturers ignored the FDA approval requirement. The unapproved drugs have names and packaging that look just like approved drugs and they are even in the Physicians' Desk Reference.

For example, the FDA ordered a number of manufacturers to stop marketing unapproved drugs that contain quinine, which is often used to treat leg cramps. The agency said it has received 665 reports of serious adverse events associated with quinine use since 1969, including 93 deaths. Among the side effects of quinine are cardiac arrhythmias, thrombocytopenia and severe hypersensitivity reaction.

Posted: 7/21/2010 12:46:00 PM

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Flame Retardant May Up Risk of Thyroid Problems in Pregnancy

From HealthDay News:

Exposure to flame-retardant chemicals may reduce a pregnant woman's levels of certain thyroid hormones that play a critical role in fetal brain development, a new study shows.

Polybrominated diphenyl ether (PBDE) flame retardants are used in a large number of consumer products, including cars, electronics and home furnishings. PBDEs are found in the blood of most Americans, according to data collected by the U.S. Centers for Disease Control and Prevention.

In the new study, published online June 21 and in an upcoming print issue of the journal Environmental Health Perspectives, researchers from the University of California, Berkeley, measured thyroid hormone levels in 270 women, most of them Mexican-American, and found that those with higher PBDE levels had lower levels of thyroid-stimulating hormone.

Women with the highest levels of the flame retardant in their blood were more likely to have subclinical hyperthyroidism, which is defined as below-normal levels of thyroid-stimulating hormone with normal levels of the thyroid hormone thyroxine (T4) , the researchers found.

"Elevated T4 in pregnancy has been associated with increased risks of miscarriage, premature birth and intrauterine growth retardation," study co-author Brenda Eskenazi added.

"A mother's thyroid hormones affect her developing baby throughout her pregnancy, and they are essential for fetal brain development," Eskenazi, director of the Center for Children's Environmental Health Research, stated in the news release.

Posted: 7/1/2010 4:10:00 PM

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