OnLine First

[Michael Scally MD]

Two landmark contraceptive efficacy studies of testosterone induced azoospermia and severe oligozoospermia conducted by WHO (World Health Organization) in 1990s showed conclusively that when spermatogenesis is severely suppressed by exogenous intramuscular administration of testosterone in healthy men, contraceptive efficacy comparable to hormonal contraceptive methods for women can be achieved. Since then three contraceptive efficacy studies have been conducted that confirmed the effectiveness of hormonal male contraception. These have been supported by the Chinese Government, WHO, and other non-government organizations. However, it should be noted that the majority of men participating in these more recent contraceptive efficacy studies originated from China.

Ethnicity is an important consideration for the development of a universally applicable male hormonal contraceptive that can be utilized throughout both the developed and developing world. Potential ethnic influences include acceptability of the method by men and their partners; ease of use of certain regimens and delivery methods (e.g. injections versus other pills); rapidity or extent of suppression of sperm output; effectiveness of suppression of spermatogenesis by different hormonal regimens; and reversibility of spermatogenesis after cessation of male hormonal contraception. Whether optimization of treatment regimens or dosages of the steroid hormones can overcome these ethnic differences is unclear. In this review, they have elected to focus on the influence of ethnicity on male contraceptive development and highlight the leadership role of East Asian investigators and the supportive government and non-government organizations in accelerating progress of this field. For the purpose of this review, East Asian men refer to men mainly from China and Indonesia and Caucasian men refer to white men with European ancestry. In addition, they use efficacy for contraceptive efficacy and effectiveness to denote adequate suppression of sperm concentration to levels that are compatible with contraceptive efficacy.


Ilani N, Liu PY, Swerdloff RS, Wang C. Does ethnicity matter in male hormonal contraceptive efficacy? Asian J Androl. Does ethnicity matter in male hormonal contracepti... [Asian J Androl. 2011] - PubMed result

The development of male hormonal contraception has progressed significantly during the last three decades. The ultimate goal is to produce an effective, safe and reversible male method of contraception that are within reach of and can be used by all men globally. This review aims to outline the recent developments in male hormonal contraception with special emphasis on how ethnicity influences acceptability, extent of sperm suppression, and rate of recovery of spermatogenesis. Baseline differences in testicular histomorphology and testosterone metabolism between East Asian and Caucasian men have been reported, but whether this contributes significantly to varying degrees of sperm suppression in response to exogenous testosterone therapy is less known. Testosterone alone male hormonal contraceptive regimens are effective and applicable for East Asian men, and less so for Caucasians. Combinations of progestins with androgens are sufficient to optimize effectiveness of suppression and applicability to all ethnicities. New compounds such as steroidal or non-steroidal selective androgen receptor modulators with dual androgenic and progestational activities are potential compounds for further development as male hormonal contraceptive methods. At the present time, combined androgen and progestin contraceptive regimens appear to be effective, safe, reversible and convenient to use for all men with ethnic, cultural and environmental differences. Further refinements on the hormonal agent, methods of delivery, and dose optimization of the androgen relative to the progestin are necessary. This goal mandates further investment and large clinical trials in multiethnic populations to better define safety and efficacy.

 

[Michael Scally MD]

[Note: This study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal. Also, the FDA recently denied a label extension for the drug.]

Effect of dutasteride on prostate cancer progression and cancer diagnosis on rebiopsy in the REDEEM active surveillance study.
Effect of dutasteride on prostate cancer progression and cancer diagnosis on rebiopsy in the REDEEM active surveillance study. - ASCO

Citation: J Clin Oncol 29: 2011 (suppl 7; abstr 2)

Author(s): N. Fleshner, M. S. Lucia, K. Melich, I. M. Nandy, L. Black, R. S. Rittmaster; University Health Network, Toronto, ON, Canada; University of Colorado School of Medicine, Aurora, CO; GlaxoSmithKline, Research Triangle Park, NC

Background: The REDEEM (Reduction by Dutasteride of Clinical Progression Events in Expectant Management of Prostate Cancer) study tested whether dutasteride controlled growth of existing low risk, localized prostate cancer (PCa) and hence reduced the need for aggressive therapy in men followed with active surveillance.

Methods: 302 men, aged 48-82, with PSA <11 ng/ml, and Gleason score ?6 PCa (?3 cores positive, <50% of any core positive) were randomized to dutasteride or placebo for 3 years. Repeat 12-core biopsies were performed at 18 and 36 months, or for-cause at other times during the study. The primary endpoint was time to progression, defined as the earliest of either pathological progression (Gleason score >6, ?4 cores positive, or >50% of any core positive) or therapeutic progression (radical prostatectomy, radiation therapy, or hormonal ablation).

Results: 96% of subjects reached the primary endpoint or had a post-baseline biopsy. Dutasteride reduced time to PCa progression (relative risk reduction 38.9%, 95% CI: 12.4-57.4%, P=0.007). The table presents incidence of progression and Gleason score on final biopsy. 23% of men (N=31) in the placebo group and 36% of men (N=50) in the dutasteride group had no cancer detected on their final biopsy. PCa-related anxiety was reduced in the dutasteride arm compared to the placebo arm (P=0.036), based on the Memorial Anxiety Scale for PCa (MAX-PC). Drug-related adverse events were similar to those previously reported for dutasteride.

Conclusions: In men followed with active surveillance, dutasteride delayed the time to PCa progression, increased the percent of men with no detectable PCa, and improved PCa-related anxiety. There was no evidence of increased Gleason score upgrading with dutasteride. Dutasteride may provide a useful adjunct to active surveillance for management of PCa.

 

[Michael Scally MD]

To investigate whether there is an additional association between overweight and obesity and the risk of coronary heart disease (CHD), researchers related baseline body mass index (BMI) to the risk of incident events in the West of Scotland Coronary Prevention Study (WOSCOPS). Fatal and non-fatal CHD events were also examined separately in 15 years of follow-up data for this moderate-risk cohort. These hypothesis generating data suggest that obesity is associated with fatal, but not non-fatal, CHD after accounting for known cardiovascular risk factors and deprivation.


Logue J, Murray HM, Welsh P, et al. Obesity is associated with fatal coronary heart disease independently of traditional risk factors and deprivation. Heart. Obesity is associated with fatal coronary heart disease independently of traditional risk factors and deprivation -- Logue et al. -- Heart

Background - The effect of body mass index (BMI) on coronary heart disease (CHD) risk is attenuated when mediators of this risk (such as diabetes, hypertension and hyperlipidaemia) are accounted for. However, there is now evidence of a differential effect of risk factors on fatal and non-fatal CHD events, with markers of inflammation more strongly associated with fatal than non-fatal events.

Objective - To describe the association with BMI separately for both fatal and non-fatal CHD risk after accounting for classical risk factors and to assess any independent effects of obesity on CHD risk.

Methods and results - In the West of Scotland Coronary Prevention Study BMI in 6082 men (mean age 55 years) with hypercholesterolaemia, but no history of diabetes or CVD, was related to the risk of fatal and non-fatal CHD events. After excluding participants with any event in the first 2 years, 1027 non-fatal and 214 fatal CHD events occurred during 14.7 years of follow-up. A minimally adjusted model (age, sex, statin treatment) and a maximally adjusted model (including known CVD risk factors and deprivation) were compared, with BMI 25–27.4 kg/m2 as referent. The risk of non-fatal events was similar across all BMI categories in both models. The risk of fatal CHD events was increased in men with BMI 30.0–39.9 kg/m2 in both the minimally adjusted model (HR=1.75 (95% CI 1.12 to 2.74)) and the maximally adjusted model (HR=1.60 (95% CI 1.02 to 2.53)).

Conclusions - These hypothesis generating data suggest that obesity is associated with fatal, but not non-fatal, CHD after accounting for known cardiovascular risk factors and deprivation.

 

[Michael Scally MD]

The study purpose was to determine the effects of a commercially available product (Trigonella foenumgraecum [standardized for Grecunin]) purported to inhibit aromatase and 5-alpha reductase activity on strength, body composition, and hormonal profiles in resistance-trained men during an 8-week resistance-training program. This work was funded by Indus Biotech who supplied the supplements! They were then randomly assigned in a double-blind manner to ingest capsules containing 500 mg of placebo (maltodextrin; PL) or 500 mg of T. foenum-graecum (standardized for Grecunin; AI; Indus Biotech, India).


Wilborn C, Taylor L, Poole C, Foster C, Willoughby D, Kreider R. Effects of a purported aromatase and 5alpha-reductase inhibitor on hormone profiles in college-age men. Int J Sport Nutr Exerc Metab 2010;20(6):457-65. http://esnl.tamu.edu/Publications/Wilborn%20et%20al%20IJSNEM%202010.pdf

The purpose of this study was to determine the effects of an alleged aromatase and 5-alpha reductase inhibitor (AI) on strength, body composition, and hormonal profiles in resistance-trained men. Thirty resistance-trained men were randomly assigned in a double-blind manner to ingest 500 mg of either a placebo (PL) or AI once per day for 8 wk. Participants participated in a 4-d/wk resistance-training program for 8 wk. At Weeks 0, 4, and 8, body composition, 1-repetition-maximum (1RM) bench press and leg press, muscle endurance, anaerobic power, and hormonal profiles were assessed. Statistical analyses used a 2-way ANOVA with repeated measures for all criterion variables (p </= .05). Significant Group x Time interaction effects occurred over the 8-wk period for percent body fat (AI: -1.77% +/- 1.52%, PL: -0.55% +/- 1.72%; p = .048), total testosterone (AI: 0.97 +/- 2.67 ng/ml, PL: -2.10 +/- 3.75 ng/ml; p = .018), and bioavailable testosterone (AI: 1.32 +/- 3.45 ng/ml, PL: -1.69 +/- 3.94 ng/ml; p = .049). Significant main effects for time (p </= .05) were noted for bench- and leg-press 1RM, lean body mass, and estradiol. No significant changes were detected among groups for Wingate peak or mean power, total body weight, dihydrotestosterone, hemodynamic variables, or clinical safety data (p > .05). The authors concluded that 500 mg of dailyAI supplementation significantly affected percent body fat, total testosterone, and bioavailable testosterone compared with a placebo in a double-blind fashion.

 

[Michael Scally MD]

According to research appearing online in the journal PLoS One, "mouse researchers conducting stress hormone experiments have stumbled onto a surprising new discovery -- a potential treatment for hair loss." "Scientists were using genetically engineered mutant mice that were altered to produce too much of a stress hormone called corticotrophin-releasing factor, or CRF." The mice had no hair on their backs due to the chronic stress condition caused by CRF. The researchers "injected a chemical compound called astressin-B, developed by the California-based Salk Institute, into the mice to see how the CRF-blocker would affect gastrointestinal function." Three months later, the stressed-out mice "had regrown all the hair they had lost." "Further tests showed the treatment to work much better than minoxidil, one of the drugs of choice in treating hair loss." The researchers now plan to find out "just how the drug triggers regrowth, ahead of tests on people," which are at least five years away.

The CRF1/CRF2 receptor antagonist, astressin-B, injected intraperitoneally (ip) in CRF-OE mice with fully developed alopecia induces hair growth and pigmentation. Photographs:
Row A: Male CRF-OE mice (4 months old) injected ip once daily for 5 consecutive days with saline at 3 days after the last injection and
Row B: astressin-B (5 mg/mouse) at 3 days after the last ip injection, and
Row C: the same mice as in the middle panel Row B at 4 weeks after the last ip injection.


Wang L, Million M, Rivier J, et al. CRF Receptor Antagonist Astressin-B Reverses and Prevents Alopecia in CRF Over-Expressing Mice. PLoS ONE 2011;6(2):e16377. PLoS ONE: CRF Receptor Antagonist Astressin-B Reverses and Prevents Alopecia in CRF Over-Expressing Mice

Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4–9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF2 receptor antagonist, astressin2-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.

 

[Michael Scally MD]

In the 1958 film Live Fast and Die Young, two reckless sisters threaten to burn out early. Similarly, one theory of aging predicts that a faster metabolism leads to a shorter life. Does this trade-off also apply to age-related disease? A new study by Guevara-Aguirre et al. offers clues that address this seminal question. The authors’ findings stem from studies of a unique group of Ecuadorian people who have a mutation in the growth hormone receptor (GHR) gene and a resulting insulin-like growth factor–1 (IGF-1) deficiency, which stunts their growth. These descendants of Spanish conversos, Jews who converted to Christianity to avoid the Inquisition, almost never get diabetes or cancer as a result, the authors postulate, of the privileged metabolic status that arises from their altered hormonal state. Relative to controls, these subjects show lower insulin concentrations and higher insulin sensitivity, and when stressed, their cells tend to self-destruct rather than accumulate mutations and DNA damage—all features that are known to promote cell protection in model organisms.

For 22 years, this group of 99 related Ecuadorians—most of whom are homozygous for an A-to-G splice site mutation at position 180 in exon 6 of the GHR gene—has been monitored extensively, so that their health details are well documented. From this reservoir of data, plus information about the diseases of family members as well as causes of death of those relatives who have died, the authors deciphered that the Ecuadorian subjects who carried the GHR mutation had an abnormally low incidence of cancer and diabetes. The group showed only one case of nonlethal cancer and no cases of diabetes, whereas the controls—unaffected relatives—developed cancer (17%) and diabetes (5%) at rates similar to those of the Ecuadorian population as a whole.

To illuminate the underlying reason for the subjects’ freedom from these diseases, the authors focused on the components carried in their blood. In experiments on cultured human epithelial cells, Guevara-Aguirre et al. found that low concentrations of one of these, IGF-1, was responsible for preventing oxidative DNA damage when the cells were exposed to the oxidizing agent H2O2 and for promoting cell death when stress-related DNA damage did occur, a checkpoint that averts cancer-promoting behavior by abnormal cells. Analysis of the participating cell signaling pathways identified activation of the transcription factor FoxO under conditions of low IGF-1 as a likely mediator of these effects. Further, the lower blood insulin concentrations and higher insulin sensitivity in these subjects likely account for the absence of diabetes in this population.

Although it is difficult to prove that alterations in IGF-1 amounts are responsible for the cancer- and diabetes free lives of these Ecuadorian people, genetic work from several model organisms suggests that this is so. In yeast, mutations in genes that encode components of a growth-promoting pathway protect against age-dependent genomic instability, and mutations in the insulin/IGF-1–like signaling pathway increase life span and reduce abnormal cellular proliferation in worms. Mice with defects in GH and IGF-1 live exceptionally long lives, with delayed appearance of age-dependent mutations and cancer. The Ecuadorians do not live longer-than-normal lives compared with their compatriots, but rather die in due course from causes of death other than cancer and diabetes complications. Thus, the metabolic inverse of “live fast and die young”—a slowed metabolism yields a longer life— is not supported by the current findings. But a life free from two dreaded diseases may be considered a desirable trade-off.

Ecuadorean Villagers May Hold Secret to Longevity
http://www.nytimes.com/2011/02/17/science/17longevity.html

[This is contrary to the whole idea and theory for the use of hGH in "anti-aging." It is also supportive of the reports showing an increased cancer risk with IGF-1. As I have posted here, do NOT jump on the hGH wagon so quickly! Note what is stated about insulin resistance.]

By NICHOLAS WADE
Published: February 16, 2011

People living in remote villages in Ecuador have a mutation that some biologists say may throw light on human longevity and ways to increase it.

The villagers are very small, generally less than three and a half feet tall, and have a rare condition known as Laron syndrome or Laron-type dwarfism. They are probably the descendants of conversos, Sephardic Jews from Spain and Portugal who were forced to convert to Christianity in the 1490s but were nonetheless persecuted in the Inquisition. They are also almost completely free of two age-related diseases, cancer and diabetes.

A group of 99 villagers with Laron syndrome has been studied for 24 years by Dr. Jaime Guevara-Aguirre, an Ecuadorean physician and diabetes specialist. He discovered them when traveling on horseback to a roadless mountain village. Most such villages are inhabited by Indians, but these were Europeans, with Spanish surnames typical of conversos.

As Dr. Guevara-Aguirre accumulated health data on his patients, he noticed a remarkable pattern: though cancer was frequent among people who did not have the Laron mutation, those who did have it almost never got cancer. And they never developed diabetes, even though many were obese, which often brings on the condition.

“I discovered the population in 1987,” Dr. Guevara-Aguirre said in an interview from Ecuador. “In 1994, I noticed these patients were not having cancer, compared with their relatives. People told me they are too few people to make any assumption. People said, ‘You have to wait 10 years,’ so I waited. No one believed me until I got to Valter Longo in 2005.”

Valter D. Longo, a researcher on aging at the University of Southern California, saw the patients as providing an opportunity to explore in people the genetic mutations that researchers had found could make laboratory animals live much longer than usual.

The Laron patients have a mutation in the gene that makes the receptor for growth hormone. The receptor is a protein embedded in the membrane of cells. Its outside region is recognized by growth hormone circulating through the body; the inside region sends signals through the cell when growth hormone triggers the receptor.

The Laron patients’ mutation means that their growth hormone receptor lacks the last eight units of its exterior region, so it cannot react to growth hormone. In normal children, growth hormone makes the cells of the liver churn out another hormone, called insulinlike growth factor, or IGF-1, and this hormone makes the children grow. If the Laron patients are given doses of IGF-1 before puberty, they can grow to fairly normal height.

This is where the physiology of the Laron patients links up with the longevity studies that researchers have been pursuing with laboratory animals. IGF-1 is part of an ancient signaling pathway that exists in the laboratory roundworm as well as in people. The gene that makes the receptor for IGF-1 in the roundworm is called DAF-2. And worms in which this gene is knocked out live twice as long as normal.

The Laron patients have the equivalent defect — their cells make very little IGF-1, so very little IGF-1 signaling takes place, just as in the DAF-2-ablated worms. So the Laron patients might be expected to live much longer.

Because of their striking freedom from cancer and diabetes, they probably could live much longer if they did not have a much higher than usual death rate from causes unrelated to age, like alcoholism and accidents.

Dr. Longo said he believed that having very low levels of IGF-1 was the critical feature of the Laron patients’ freedom from age-related diseases. In collaboration with Dr. Guevara-Aguirre, he exposed human cells growing in a laboratory dish to serum from the Laron patients. The cells were then damaged with a chemical that disrupts their DNA. The Laron serum had two significant effects, the two physicians reported on Wednesday in Science Translational Medicine.

First, the serum protected the cells from genetic damage. Second, it spurred the cells that were damaged to destroy themselves, a mechanism the body uses to prevent damaged cells from becoming cancerous. Both these effects were reversed when small amounts of IGF-1 were added to the serum.

Dr. Longo said that some level of IGF-1 was necessary to protect against heart disease, but that lowering the level might be beneficial. A drug that does this is already on the market for treatment of acromegaly, a thickening of the bones caused by excessive growth hormone. “Our underlying hypothesis is that this drug would prolong life span,” Dr. Longo said. He said he was not taking the drug, called pegvisomant or Somavert, which is very hard to obtain.

A strain of mice bred by John Kopchick of Ohio University has a defect in the growth hormone receptor gene, just as do the Laron patients, and lives 40 percent longer than usual.

Dr. Longo said that his report had first been submitted to Science, a better-known journal, which turned down the paper because of an adverse report from one reviewer.

Andrzej Bartke, a gerontology expert at Southern Illinois University, said that the new result was “very important” and that the authors had done a fine job in following the patients and generating high-quality data. “This fits in with what we are learning from studies in animals about the relationship of growth hormone to aging, because both cancer and diabetes are related to aging,” Dr. Bartke said.

The longest-lived mouse on record is one studied by Dr. Bartke. It had a defect in its growth hormone receptor gene, just as do the Laron patients. “It missed its fifth birthday by a week,” he said. The mouse lived twice as long as usual and won Dr. Bartke a prize presented by the Methuselah Foundation (which rewards developments in life-extension therapies) in 2003.

Dr. Guevara-Aguirre said he had been struggling to get sufficient IGF-1 to treat 30 of his patients before they reached puberty, at which point it will be too late. He said his group of Laron patients, the largest in the world, had provided essential data for drug companies making IGF-1, and he chided the companies for not reciprocating by providing the drug for his patients.

Dr. Arlan Rosenbloom, a pediatric endocrinologist at the University of Florida who has worked with Dr. Guevara-Aguirre, took a similar position. “Considering that the drug companies needed the initial studies to determine dosage and efficacy, it seems ironic that we should have so much difficulty getting the drug,” he said.

Ownership of the drug has passed through several companies’ hands, so any initial obligation may have been weakened. Dr. Guevara-Aguirre also said he believed that the government of Ecuador should do more to help get the drug for his patients.

Dr. Harry Ostrer, a geneticist at New York University who is exploring the Laron patients’ degree of Sephardic ancestry, said that he had seen several of Dr. Guevara-Aguirre’s patients in Quito, Ecuador’s capital, and that they were “remarkably youthful in appearance.”


Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans. Science Translational Medicine 2011;3(70):70ra13. Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans — Sci TM

Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 ?U/ml versus 4.4 ?U/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.

 

[Michael Scally MD]

U.S. officials released the annual state-of-the-nation's health report.

On the positive side, life expectancy was up slightly in 2007, to 77.9 years from 76.8 years at the beginning of the decade.

More troubling, are climbing obesity rates, with two-thirds of adults now overweight or obese, up from 29.9 percent a decade ago. While obesity rates among 2- to 5-year-olds seem to be leveling off, rates among older children and teens are still increasing, the report showed.

Other risk factors for chronic illnesses, including heart disease, aren't looking too good, either. Heart disease and cancer remain the two leading killers, collectively accounting for nearly half of the 2.5 million deaths in the United States in 2007, 25 percent and 23 percent, respectively.


Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2009
http://www.cdc.gov/nchs/data/series/sr_10/sr10_249.pdf

Series 10: Data From the National Health Interview Survey
No. 249

This report presents health statistics from the 2009 National Health Interview Survey for the civilian noninstitutionalized adult population, classified by sex, age, race and ethnicity, education, family income, poverty status, health insurance coverage, marital status, and place and region of residence. Estimates are presented for selected chronic conditions and mental health characteristics, functional limitations, health status, health behaviors, health care access and utilization, and human immunodeficiency virus testing. Percentages and percent distributions are presented in both age adjusted and unadjusted versions.

 

[Michael Scally MD]

Recent studies suggest that vitamin D (Vit-D), primarily important for calcium homeostasis and bone metabolism, influences the cardiovascular system through unclear mechanisms. Suboptimal Vit-D status is associated with increased all-cause and cardiovascular disease (CVD) mortality, coronary heart disease, and various cardiovascular risk factors. Serum 25-hydroxyvitamin D[25(OH)D] concentration is widely held to be a better indicator of Vit-D status than the more functionally active form, 1, 25-dihydroxyvitamin D [1,25(OH)2D or calcitriol]. Although there is no consensus on the optimal serum 25(OH)D concentration, most experts recommend an optimal concentration greater than 30 ng/ml. [I recommend 50 ng/mL.] Vit-D deficiency is even more prevalent among type 2 diabetes mellitus (DM) patients.

Endothelial dysfunction predicts cardiovascular events and represents an underlying event for vascular abnormalities observed in type 2 DM patients. The circulating endothelial progenitor cell (EPC) count has also been proposed as a surrogate marker of vascular dysfunction and is reduced in patients with various cardiovascular risk factors. The relationship between suboptimal Vit-D status, endothelial function, and circulating EPCs in type 2DM patients has not been investigated. In this study, researchers investigated the relationship between Vit-D status with endothelial function and circulating EPCs in type 2 DM patients.


Yiu Y-F, Chan Y-H, Yiu K-H, et al. Vitamin D Deficiency Is Associated with Depletion of Circulating Endothelial Progenitor Cells and Endothelial Dysfunction in Patients with Type 2 Diabetes. J Clin Endocrinol Metab:jc.2010-212. Vitamin D Deficiency Is Associated with Depletion of Circulating Endothelial Progenitor Cells and Endothelial Dysfunction in Patients with Type 2 Diabetes -- Yiu et al., 10.1210/jc.2010-2212 -- Journal of Clinical Endocrinology & Metabolism

Context - Vitamin D (Vit-D) deficiency is associated with type 2 diabetes mellitus (DM) and endothelial dysfunction. The relationship of Vit-D deficiency with circulating endothelial progenitor cells and endothelial dysfunction in type 2 DM patients nonetheless remains unclear.

Objective - We aimed to investigate the cross-sectional association of Vit-D status with brachial flow-mediated dilation (FMD) and circulating endothelial progenitor cell (EPC) numbers in type 2 DM patients.

Design, Setting, and Participants - We conducted a cross-sectional study of 280 patients (59% male, aged 68 {+/-} 10 yr) with type 2 DM recruited in outpatient clinics during the winter period.

Main Outcome Measure - We measured serum 25-hydroxyvitamin D [25(OH)D] by an ELISA kit, circulating CD34+/kinase insert domain-containing receptor (KDR)+ and CD133+/KDR+ EPCs by flow cytometry and brachial artery FMD by vascular ultrasound, respectively.

Results - The mean serum 25(OH)D concentration was 25.00 {+/-} 9.17 ng/ml, and 34.3% of patients had Vit-D deficiency [25(OH)D < 20 ng/ml]. Serum 25(OH)D concentration had a significant correlation with hemoglobin A1c level [B = -0.018, 95% confidence interval (CI) -0.035 to -0.002, P = 0.032]. Patients with Vit-D deficiency status had significantly lower brachial FMD (mean difference -1.43%, 95% CI -2.31 to -0.55, P = 0.001) and CD133+/KDR+EPC counts (mean difference -0.12%, 95% CI -0.21 to -0.019, P = 0.022) than those with sufficient Vit-D status after adjustment for age, sex, and cardiovascular risk factors, including hemoglobin A1c levels.

Conclusions - Our results demonstrate that serum 25(OH)D status was significantly associated with brachial artery FMD and circulating CD133+/KDR+EPCs. This suggests that Vit-D deficiency might contribute to depletion of EPCs and endothelial dysfunction in patients with type 2 DM.

 

[Michael Scally MD]

Model For The Mechanism Of The Anabolic Action Of Steroid Hormones

At a time when the increase in muscle mass had already become apparent, researchers interrogated high-throughput gene expression data from muscle samples using two recently published co-expression based network inference approaches called Partial Correlation coefficient with Information Theory (PCIT) and Regulatory Impact Factor (RIF), and the promoter structure of the differentially expressed genes. Their results point to a dramatic and unexpected induction of muscle oxytocin (OXT) expression also measurable in the plasma at the protein level. They hypothesise that the increased expression of OXT may account for the increased muscle mass.

Estrogen and androgen bind to intracellular receptors, which in turn bind to promoter regions of specific genes to either induce or repress expression of the primary response to steroid treatment. Muscle is composed of a mixture of cell types, which are likely to respond differently to the exposure to steroids.

As part of the response, a group of fat metabolism genes is down-regulated via an unknown mechanism, which may simply reflect a decrease in the lipid storage activity of intramuscular adipocytes due to the increased bio-energetic demand of supporting enhanced muscle growth. Also as part of the response, a group of genes encoding collagen subunits is up-regulated by an unknown mechanism, probably in the mature muscle cells. It is most likely that the increase in cell cycle gene expression occurs in the muscle satellite cells, as differentiated muscle cells do not divide and the activity of adipocytes storing lipid is decreased, which is not consistent with increased cell numbers.

The small increase in expression of IGF1 is consistent with IGF1 playing a role in the increase in muscle growth. However, the Regulatory Impact analysis (RIF) analysis more strongly supports the oxytocin receptor, OXTR, than the IGF1 receptor IGF1R, as a key driver in the phenotype induced by the steroid treatment. The signalling cascade downstream of the receptor remains somewhat enigmatic. Based on the experiments described here a much more comprehensive and more detailed picture is now available of the mechanisms by which the steroid treatment leads to the observed phenotypes of increased average daily gain.

Future studies should evaluate the association between increased OXT levels and other traits related to Hormone Growth Promotant (HGP) treatment including increased bone density, increased meat toughness and reduced intramuscular fat content. It is likely that these mechanisms will be at least partially applicable across the mammals. There are still many gaps in our understanding, not the least of which is, does oxytocin alone have an anabolic activity?

Schematic diagram of a possible mechanism whereby the sex-steroid hormones trenbolone acetate and estradiol could drive skeletal muscle growth. The solid lines represent direct actions for which the authors have supporting evidence and the broken lines represent either indirect actions or incomplete evidence. Double headed arrows indicate known protein-protein interactions.


De Jager N, Hudson NJ, Reverter A, et al. Chronic exposure to anabolic steroids induces the muscle expression of oxytocin and a more than fifty fold increase in circulating oxytocin in cattle. Physiol Genomics. http://physiolgenomics.physiology.org/content/early/2011/02/15/physiolgenomics.00226.2010.abstract

Molecular mechanisms in skeletal muscle associated with anabolic steroid treatment of cattle are unclear and we aimed to characterise transcriptional changes. Cattle were chronically exposed (68 ± 20 days) to a steroid hormone implant containing mg trenbolone acetate and 20mg estradiol (Revalor-H). Biopsy samples from 48 cattle (half treated) from Longissimus dorsi muscle (LD) under local anaesthesia were collected and gene expression levels were profiled by microarray, covering 44 unique bovine genes. One hundred and twenty one genes were differentially expressed (DE) due to the implant (99.99% posterior probability of not being false positives). Among DE genes, a decrease in expression of a number of fat metabolism associated genes, likely reflecting the lipid storage activity of intramuscular adipocytes, was observed. The expression of IGF1 and genes related to the extra-cellular matrix, slow twitch fibres and cell cycle (including SOX8, a satellite cell marker) was increased in the treated muscle. Unexpectedly, a very large 21- (microarray) to 97- (real time quantitative PCR) fold higher expression of the mRNA encoding the neuropeptide hormone oxytocin was observed in treated muscle, We also observed an ~50-fold higher level of circulating oxytocin in the plasma of treated animals at the time of biopsy. Using a co-expression network strategy OXTR was identified as more likely than IGF1R to be a major mediator of the muscle response to Revalor-H. A re-investigation of in vivo cattle LD muscle samples during early to mid-fetal development identified a > fold increased expression of OXT, coincident with myofibre differentiation and fusion. We propose that oxytocin may be involved in mediating the anabolic effects of Revalor-H treatment.

 

[Michael Scally MD]

In view of the still progressing epidemic of childhood obesity throughout the world and the positive association between childhood obesity and obesity in young adulthood, it is important to get solid estimates of the lifelong health impact of this condition. The aim of this study is to examine the association between obesity present in early adulthood and morbidity, including fatal morbidity, and all-cause mortality throughout adult life in men.


Zimmermann E, Holst C, Sorensen TI. Lifelong doubling of mortality in men entering adult life as obese. Int J Obes (Lond). Lifelong doubling of mortality in men entering adu... [Int J Obes (Lond). 2011] - PubMed result

Background: The association between obesity in adults and excess morbidity and mortality is well established, but the impact of being obese in early adulthood on health throughout adult life needs elucidation. We investigated the all-cause mortality until 80 years of age in men starting adult life as obese.

Methods: Among 362 200 Danish young men, examined for military service between 1943 and 1977, all obese (defined as body mass index (BMI)>/=31.0 kg m(-2)), and, as controls, a random 1% sample of the remaining population were identified. A total of 1862 obese, corresponding to all men above the 99.5 percentile in this population, and 3476 controls were included, at a median age of 19 years (range: 18-25 years of age). They were followed until 2007 and Cox regression models were used to estimate the mortality in the obese relative to the controls. In addition, two reference groups were used: normal weight men (BMI: 18.5-24.9 kg m(-2)) and the men with the lowest mortality in this cohort (BMI: 22.0-24.9 kg m(-2)).

Results: During the 65 years of follow-up, 1191 men died. At all ages from 18 to 80 years, the mortality in the obese was twice that of the controls (hazard ratio (HR): 2.10; 95% confidence interval (CI): 1.84-2.39). The median survival proportion (0.5) was reached about 8 years earlier in the obese than in either of the reference groups. Relative to the normal weight and men with the lowest mortality HRs of 2.14 (95% CI: 1.86-2.45) and 2.38 (95% CI: 2.00-2.85), respectively, were estimated for the obese. Neither year of birth nor education significantly influenced the excess mortality.

Conclusion: Men entering adult life as obese experience a lifelong doubling of mortality, a finding that strongly supports the continued need to avoid beginning adult life as obese.

 

[Michael Scally MD]

Opioid Induced Androgen Deficiency, OPIAD

Awareness of the need to adequately treat pain, particularly chronic pain, is slowly increasing among patients and pain therapists. Opioids are among the most prescribed analgesic drugs but present several side effects such as nausea, itching, constipation and hypogonadism. For hypogonadism, there is clear evidence in the literature for both humans and experimental animals. Symptoms and signs related to gonadal hypofunction and consequent testosterone depletion include peripheral effects (muscle hypotrophy, bone loss, anaemia, etc.) and severe and disabling central effects (decreased attention, disappearance of libido, depressive state, etc.). Moreover, there is much evidence for a close relationship between testosterone and neuroprotective processes. For instance, it was reported that older men with low levels of free circulating testosterone appear to be at higher risk of developing Alzheimer Disease than men with higher levels of this hormone, and gonadal and adrenal androgen levels were found to be lower in men and women suffering from rheumatoid arthritis than in healthy controls. In experimental animals, testosterone administration in inflammatory painful conditions, such as formalin- or adjuvant-induced pain, was found to decrease pain-induced responses.

Opioid-induced hypogonadism in males (Opioid-Induced Androgen Deficiency, OPIAD) is usually ignored by pain physicians and rarely considered for treatment despite its high frequency (almost 100%) and persistence. Daniell described the beneficial effects of testosterone replacement in opioid-treated patients for six months. The aim of the present study was to describe the time course/interactions between opioids and testosterone replacement therapy in a clinical sample of male chronic pain patients diagnosed with OPIAD and receiving morphine via the epidural route. Testosterone was replaced via a gel formulation.

Testosterone and its related hormones (estradiol, DHT) were measured in the blood, together with cortisol as an index of adrenal activity. Pain intensity and its features were studied with the VAS, the Italian version of the McGill Questionnaire (QUID) and the Margolis method to determine the percentage of the body in pain. The andrological condition was studied with the dedicated questionnaire Ageing Males’ Symptoms Scale (AMS), and different aspects of the psychological characteristics were evaluated through questionnaires able to study anxiety, depression and quality of life (POMS, CES-D and SF-36). The study was carried out for 12 months. The results suggest beneficial effects on the patients’ quality of life.


Aloisi A, Ceccarelli I, Carlucci M, Suman A, Sindaco G, Mameli S, Paci V, Ravaioli L, Passavanti G, Bachiocco V, Pari G. Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients. Reproductive Biology and Endocrinology 2011, 9:26 (18 February 2011). http://www.rbej.com/content/pdf/1477-7827-9-26.pdf

Background - In male patients suffering from chronic pain, opioid administration induces severe hypogonadism, leading to impaired physical and psychological conditions such as fatigue, anaemia and depression. Hormone replacement therapy is rarely considered for these hypogonadic patients, notwithstanding the various pharmacological solutions available.

Methods - To treat hypogonadism and to evaluate the consequent endocrine, physical and psychological changes in male chronic pain patients treated with morphine (epidural route), we tested the administration of testosterone via a gel formulation for one year. Hormonal (total testosterone, estradiol, free testosterone, DHT, cortisol), pain (VAS and other pain questionnaires), andrological (Ageing Males' Symptoms Scale - AMS) and psychological (POMS, CES-D and SF-36) parameters were evaluated at baseline (T0) and after 3, 6 and 12 months (T3, T6, T12 respectively).

Results - The daily administration of testosterone increased total and free testosterone and DHT at T3, and the levels remained high until T12. Pain rating indexes (QUID) progressively improved from T3 to T12 while the other pain parameters (VAS, Area%) remained unchanged. The AMS sexual dimension and SF-36 Mental Index displayed a significant improvement over time.

Conclusions - In conclusion, our results suggest that a constant, long-term supply of testosterone can induce a general improvement of the male chronic pain patient's quality of life, an important clinical aspect of pain management.

 

[Michael Scally MD]

There are also indications that reproductive abnormalities, expressed as cryptorchidisms, hypospadias and decreased penile length, may be linked to pesticide exposure, most strikingly in maternally exposed boys. This is significant because male fertility is thought to be declining in many countries and perinatal hypospadias/cryptorchidisms are risk factors for reduced sperm quality and testicular cancer in adulthood. The term “testicular dysgenesis syndrome” (TDS) has been proposed to explain the interrelated nature of these abnormalities.

The aim of this study was to test the anti-androgenic activity of currently used pesticides. Researchers selected compounds for testing based on evidence of human exposure (dietary intake data for Europe) and predicted AR antagonism according to the quantitative structure-activity relationship (QSAR) model. Compounds predicted to be AR antagonists and compounds with high exposure scores were analysed for AR antagonist properties using the MDA-kb2 assay. In addition, the yeast anti-androgen screen (YAS) was used to further test a subset of pesticides that were newly identified as AR antagonists or had MDAkb2 assay results that were discordant with QSAR predictions.


Orton F, Rosivatz E, Scholze M, Kortenkamp A. Widely Used Pesticides with Previously Unknown Endocrine Activity Revealed as in Vitro Anti-Androgens. Environ Health Perspect. Environmental Health Perspectives: Widely Used Pesticides with Previously Unknown Endocrine Activity Revealed as in Vitro Anti-Androgens

Background: Evidence suggests that there is widespread decline in male reproductive health and anti-androgenic pollutants may play a significant role. There is also a clear disparity between pesticide exposure and endocrine disrupting data, with the majority of the published literature focused on pesticides that are no longer registered for use in developed countries.

Objective: The aim of this study was to utilise estimated human exposure data to select pesticides to test for anti-androgenic activity, focusing on highest use pesticides.

Methods: We used European databases to select 134 candidate pesticides based on highest exposure, followed by a filtering step according to known or predicted receptor mediated anti-androgenic potency, based on a previously published quantitative structure-activity relationship (QSAR) model. In total, 37 pesticides were tested for in vitro androgen receptor (AR) antagonism. Of these, 14 were previously reported to be AR antagonists ("active"), 4 were predicted AR antagonists using the QSAR, 6 were predicted to not be AR antagonists ("inactive"), and 13 with unknown activity, which were "out of domain" and therefore could not be classified with the QSAR ("unknown").

Results: All 14 pesticides with previous evidence of AR antagonism were confirmed as anti-androgenic in our assay and 9 previously untested pesticides were identified as anti-androgenic (dimethomorph, fenhexamid, quinoxyfen, cyprodinil, lambda-cyhalothrin, pyrimethanil, fludioxonil, azinphos-methyl, pirimiphos-methyl). In addition, 7 compounds were classified as androgenic.

Conclusions: Due to estimated anti-androgenic potency, current use, estimated exposure, and lack of previous data, we strongly recommend that dimethomorph, fludioxonil, fenhexamid, imazalil, ortho-phenylphenol and pirimiphos-methyl be tested for anti-androgenic effects in vivo. The lack of human biomonitoring data for environmentally relevant pesticides presents a barrier to current risk assessment of pesticides on humans.

 

[Michael Scally MD]

Evaluation of Androgenic Activity of Nutraceutical Derived Steroids

The over-the-counter nutritional supplement (nutraceutical) market has grown rapidly since the 1994 legislation permitting sale of steroid precursors as nutraceutical food supplements with a market turnover estimated at more than US $60 billion in 2006. Nutraceuticals, claiming on their labels to enhance performance legally, are marketed to athletes. However, chemical analysis has revealed undeclared compounds in these products including substances banned by the World Anti-Doping Agency (WADA) as well as novel designer androgens or proandrogens, which are not specified in the WADA Prohibited List but generically are prohibited as androgens.

WADA-approved doping detection tests for androgens identify banned steroids using gas or liquid chromatography with tandem mass spectrometry (MS). Although sensitive and specific, these methods can only detect specified steroid structures and not their in vivo metabolites nor whether they are androgen agonists or antagonists. Hence, MS based methods alone cannot serve adequately to support the generic prohibition of androgens.

One approach to addressing these limitations has been the development of in vitro androgen bioassays, which allow for functional characterization of steroids as androgens according to their AR-specific transcriptional activity, regardless of structural knowledge. These assays entail the use of eukaryotic cells over expressing the androgen receptor (AR) and introduced with a reporter gene driven by an androgen response element. A widely used model for evaluating steroidal bioactivity is the yeast-based AR ?-galactosidase (?-gal) bioassay with recent variations using modified (yeast enhanced green fluorescent, luciferase) readout, although these display notably reduced sensitivity (EC50 10-50 nM vs ?5 nM for ?-gal). In addition, mammalian cell-based androgen bioassays developed using a mouse mammary tumour virus (MMTV) sequence driven luciferase (luc) reporter gene feature reduced specificity because the MMTV sequence contains response elements that are recognized not only by the AR but also by the progesterone (PR) and glucocorticoid (GR) receptors.

In this study, researchers developed two new, robust, and specific mammalian AR bioassays, using a novel hybrid androgen response element (ARE) driven secreted alkaline phosphatase (SEAP) reporter gene in two human cell lines. They show that their novel mammalian bioassay has higher specificity and simpler format but lower sensitivity than the MMTV luciferase format. Researchers used both mammalian bioassays to determine the androgenic potency of known androgens as well as that of nutraceutical-derived steroids in tandem with a yeast-based AR bioassay to gather insight into the contributions of different cellular formats on androgen bioassay performance.

Compounds

Capsules were obtained from Bodybuilding.com - The Future Of Bodybuilding! Huge Bodybuilding Site. via the Internet and emptied before extraction.
(i) 19-norandrost-4,9-diene-3,17- dione (Trena; Nutracoastal),
(ii) 6R-methylandrost-4-ene-3,17- dione (Formadrol; Legal Gear),
(iii) 2R,3R-epithioandrostane- 17R-methyl-17?-ol (Hemapolin; Star Mark Laboratories), and
(iv) a mixture of 17?-hydroxyandrostano[3,2-c]-isoxazole and 17?-hydroxyandrostano[2,3-d]-isoxazole isomers (Furazadrol; Axis Laboratories)

Tablets of
(v) Oxyguno [labeled ingredient 4-chloro-17R-methyl-etioallochol- 4-ene-17?-ol-3,11-dione, not isolated pure but as a mixture of steroidal components, many containing chlorine (Spectra Force)] were crushed before extraction.


Akram ON, Bursill C, Desai R, et al. Evaluation of Androgenic Activity of Nutraceutical-Derived Steroids Using Mammalian and Yeast in Vitro Androgen Bioassays. Anal Chem. Evaluation of Androgenic Activity of Nutraceutical... [Anal Chem. 2011] - PubMed result

Androgenic steroids marketed online as nutraceuticals are a growing concern in sport doping. The inability of conventional mass spectrometry (MS)-based techniques to detect structurally novel androgens has led to the development of in vitro androgen bioassays to identify such designer androgens by their bioactivity. The objective of this study was to determine the androgenic bioactivity of novel steroidal compounds isolated from nutraceuticals using both yeast and mammalian cell-based androgen bioassays.

We developed two new in vitro androgen bioassays by stably transfecting HEK293 and HuH7 cells with the human androgen receptor (hAR) expression plasmid together with a novel reporter gene vector (enhancer/ARE/SEAP). The yeast beta-galactosidase androgen bioassay was used for comparison. Our new bioassay featuring the enhancer/ARE/SEAP construct (-S) displayed simpler assay format and higher specificity with lower sensitivity compared with the commonly used mouse mammary tumour virus (MMTV)-luciferase.

The relative potencies (RP), defined as [EC(50)] of testosterone/[EC(50)] of steroid, of nutraceutical extracts in the yeast, HEK293-S, and HuH7-S, were 34, 333, and 80 000 for Hemapolin; 208, 250, and 80 for Furazadrol; 0.38, 10, and 106 for Oxyguno; 2.7, 0.28, and 15 for Trena; and 4.5, 0.1, and 0.4 for Formadrol, respectively.

The wide discrepancies in rank RP of these compounds was reconciled into a consistent potency ranking when the cells were treated with meclofenamic acid, a nonselective inhibitor of steroid metabolizing enzymes. These findings indicate that steroids extracted from nutraceuticals can be converted in vitro into more or less potent androgens in mammalian but not in yeast cells. We conclude that the putative androgenic bioactivity of a new compound may depend on the bioassay cellular format and that mammalian cell bioassays may have an added benefit in screening for proandrogens but sacrifice specificity for sensitivity in quantitation.

 

[Michael Scally MD]

The Art of Flight
This is the trailer of the new Travis Rice Project called The Art Of Flight. Follow the riders Travis Rice, John Jackson, Mark Landvik, Scotty Lago, Jake Blauvelt, Nicolas Muller, Gigi Ruf, DCP et Pat Moore progress the sport of snowboarding to unimaginable levels.
THE ART OF FLIGHT

 

[Michael Scally MD]

‘Ecstasy’, as used below, refers to illicit 3,4- methylenedioxymethamphetamine (MDMA), with the recognition that actual ‘street’ preparations may be adulterated or even contain no MDMA at all. Ecstasy has been used by some 12 million individuals in the United States alone, and millions more world-wide. An extensive animal literature suggests that ecstasy can be neurotoxic, especially to the 5-HT system, with consequent possible effects on cognitive performance, but it is unclear whether these findings can be extrapolated fully to humans. To address this question, numerous naturalistic studies have assessed cognitive function in illicit ecstasy users. These studies, reviewed in several recent papers, generally suggest that illicit ecstasy users display negative residual effects on various cognitive measures, with the most consistent and robust finding being lowered verbal memory. Such findings are of concern not only with regard to illicit ecstasy use, but for recent studies proposing therapeutic applications for MDMA, such as in the treatment of post-traumatic stress disorder.

Such naturalistic studies are vulnerable to methodological limitations, many of which might plausibly bias findings towards an overestimate of differences between ecstasy users and non-users. First, comparison non-users in many studies were not members of the ‘rave’ subculture. Thus, unlike ecstasy users, they lacked repeated exposure to sleep and fluid deprivation from all night dancing—factors that themselves can produce long-lasting cognitive effects. Secondly, few studies screened participants for MDMA, other illicit drugs and alcohol on the day of testing—leaving open the possibility of surreptitious recent drug use. Thirdly, ecstasy users in virtually all studies reported extensive life-time use of other drugs, including cannabis, amphetamine, other hallucinogens and cocaine—which might themselves contribute neurotoxicity. Studies have typically addressed this issue by statistically adjusting for other drug use or by matching groups for non-ecstasy drug use, but such methods are probably imperfect. Fourthly, cognitive difficulties in ecstasy users might be attributable to pre-morbid attributes rather than ecstasy exposure. For example, users might be less intelligent or more impulsive than non-users even before using ecstasy: possibilities that can be explored, but never eliminated, in cross-sectional studies.

To address these problems, researchers performed a 2004 pilot study assessing cognitive function in 23 ecstasy users and 16 non-users, all reporting minimal exposure to other illicit drugs or alcohol and all reporting a history of all-night dancing. They tested all participants for alcohol and illicit drugs, including MDMA, at the time of testing, and excluded positive cases. They then compared cognitive test results in non-users versus ‘moderate’ users (reporting 22–50 life-time episodes of use) versus ‘heavy’ users (60–450 episodes) while adjusting for numerous potentially confounding attributes, including age, gender, family-of-origin attributes, estimated verbal IQ and Beck Depression Inventory (BDI) scores. Moderate users exhibited virtually no significant differences versus non-users, but heavy users differed significantly from non-users on several measures, involving mental processing speed, strategic self-regulation and executive functioning. These findings seemed unlikely to represent an artifact of the methodological limitations enumerated above, as each had been addressed in the study design.

These findings were not able to be replicated in a similar larger investigation, reported here.


Halpern JH, Sherwood AR, Hudson JI, Gruber S, Kozin D, Pope Jr HG. Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs. Addiction. Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs - Halpern - 2011 - Addiction - Wiley Online Library

Aims - In field studies assessing cognitive function in illicit ecstasy users, there are several frequent confounding factors that might plausibly bias the findings toward an overestimate of ecstasy-induced neurocognitive toxicity. We designed an investigation seeking to minimize these possible sources of bias.

Design - We compared illicit ecstasy users and non-users while (1) excluding individuals with significant life-time exposure to other illicit drugs or alcohol; (2) requiring that all participants be members of the ‘rave’ subculture; and (3) testing all participants with breath, urine and hair samples at the time of evaluation to exclude possible surreptitious substance use. We compared groups with adjustment for age, gender, race/ethnicity, family-of-origin variables and childhood history of conduct disorder and attention deficit hyperactivity disorder. We provide significance levels without correction for multiple comparisons.

Setting - Field study.

Participants - Fifty-two illicit ecstasy users and 59 non-users, aged 18–45 years.

Measurements - Battery of 15 neuropsychological tests tapping a range of cognitive functions.

Findings - We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self-regulation, possibly reflecting increased impulsivity. However, this finding might have reflected a pre-morbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug.

Conclusions - In a study designed to minimize limitations found in many prior investigations, we failed to demonstrate marked residual cognitive effects in ecstasy users. This finding contrasts with many previous findings—including our own—and emphasizes the need for continued caution in interpreting field studies of cognitive function in illicit ecstasy users.

 

[Michael Scally MD]

Human axillary odor derives in part from a range of compounds known as androstenes. Following early findings that some androstenes constitute pheromones produced in boar saliva, giving rise to classic stereotyped behavior in the form of lordosis, research has attempted to establish whether androstenes affect human behavior in similar ways. Yet the question of whether there is any sense in speaking of human pheromones remains open. Some of those who consider the existence of human pheromones to be an unresolved question do so on the basis of what they see as a shortage of empirical data. The concern of others may be less to do with the specific findings (or lack of them) and more an objection based on definitional semantics, based on a preference to reserve the term ‘‘pheromone’’ for traditional releaser or primer effects. Others refute the suggestion that mammals have pheromones at all, preferring to think of them simply as social chemosignals. In this light, social odors influence behavior in the way that a peacock’s train or a human smile might do in the visual domain. Whether or not they turn out to be pheromones (if these exist in mammals), research continues into the influence of androstenes on human physiology and behavior. Studies have focused on the production of androstenes in the axillae, the biochemistry and microbiology that influence the origins of human body odor, and the impact of sex differences and puberty on these mechanisms. Others have investigated individual differences in perception, including effects of the menstrual cycle, differences in odor threshold levels, and the effects of sensitization. Finally, some researchers have directed their efforts at understanding whether androstenes impact on human mood, physiology, perception, and behavior.


Adolph D, Schlosser S, Hawighorst M, Pause BM. Chemosensory signals of competition increase the skin conductance response in humans. Physiol Behav 2011;101(5):666-71. Chemosensory signals of competition increase the s... [Physiol Behav. 2010] - PubMed result

In vertebrates, chemosensory signals of competition are communicated between conspecifics, eliciting behavioral and physiological adaptations in the perceiving animal. The current study investigates, whether chemosensory signals of competition are also communicated between humans, and whether they elicit physiological changes in the perceiver. It is further investigated whether personality traits alter this physiological responding. Axillary sweat was collected from six male donors during a competition (badminton match) and a sport control condition (running). The donors' testosterone rose stronger during the competition as compared to the sport control condition. The chemosensory stimuli were presented to 18 (9 male) participants through a constant-flow olfactometer, while the skin conductance response (SCR) was measured. Results reveal that the SCR was larger in response to chemosensory signals collected during the competition condition as compared to those collected during the sport control condition. Furthermore, regression analyses showed, that higher scores on trait social anxiety were related to larger SCRs towards the chemosensory signals of competition. The current result suggests that chemosensory signals of competition can be communicated between humans, and that they elicit orienting in the perceiving individual. These data are consistent with current research, suggesting that high socially anxious individuals process threatening social information preferentially. The current results add to the growing body of research into human chemosensory communication of social information, and extend previous research on the chemosensory communication of anxiety.

 

[Michael Scally MD]

The objective of this study was to assess if acute cell phone exposure affected regional activity in the human brain. For this purpose researchers evaluated the effects in healthy participants (N = 47) of acute cell phone exposures on brain glucose metabolism, measured using PET with injection of (18F)fluorodeoxyglucose (18FDG). Brain glucose metabolic activity is a more proximal marker of neuronal activity than measures of CBF, which reflects vascular as well as neuronal components. Also, because brain glucose metabolic measures obtained with 18FDG reflect the averaged brain activity occurring over a 30-minute period, this method allowed assessment of the cumulative effects of cell phone exposure on resting brain metabolism. Because exposure to RF-EMFs from cell phones is well localized and is highest in brain regions closest to the antenna, they hypothesized that the effects on brain metabolism would be greatest in inferior and anterior brain regions, the regions that would be exposed to the highest RF-EMF amplitude for the cell phone model used in this study.


Volkow ND, Tomasi D, Wang G-J, et al. Effects of Cell Phone Radiofrequency Signal Exposure on Brain Glucose Metabolism. JAMA: The Journal of the American Medical Association 2011;305(8):808-13. Effects of Cell Phone Radiofrequency Signal Exposure on Brain Glucose Metabolism, February 23, 2011, Volkow et al. 305 (8): 808 — JAMA

Context - The dramatic increase in use of cellular telephones has generated concern about possible negative effects of radiofrequency signals delivered to the brain. However, whether acute cell phone exposure affects the human brain is unclear.

Objective - To evaluate if acute cell phone exposure affects brain glucose metabolism, a marker of brain activity.

Design, Setting, and Participants - Randomized crossover study conducted between January 1 and December 31, 2009, at a single US laboratory among 47 healthy participants recruited from the community. Cell phones were placed on the left and right ears and positron emission tomography with (18F)fluorodeoxyglucose injection was used to measure brain glucose metabolism twice, once with the right cell phone activated (sound muted) for 50 minutes (“on” condition) and once with both cell phones deactivated (“off” condition). Statistical parametric mapping was used to compare metabolism between on and off conditions using paired t tests, and Pearson linear correlations were used to verify the association of metabolism and estimated amplitude of radiofrequency-modulated electromagnetic waves emitted by the cell phone. Clusters with at least 1000 voxels (volume >8 cm3) andP < .05 (corrected for multiple comparisons) were considered significant.

Main Outcome Measure - Brain glucose metabolism computed as absolute metabolism (?mol/100 g per minute) and as normalized metabolism (region/whole brain).

Results - Whole-brain metabolism did not differ between on and off conditions. In contrast, metabolism in the region closest to the antenna (orbitofrontal cortex and temporal pole) was significantly higher for on than off conditions (35.7 vs 33.3 ?mol/100 g per minute; mean difference, 2.4 [95% confidence interval, 0.67-4.2];P = .004). The increases were significantly correlated with the estimated electromagnetic field amplitudes both for absolute metabolism (R = 0.95,P < .001) and normalized metabolism (R = 0.89; P < .001).

Conclusions - In healthy participants and compared with no exposure, 50-minute cell phone exposure was associated with increased brain glucose metabolism in the region closest to the antenna. This finding is of unknown clinical significance.

 

[Michael Scally MD]

Editorial: Lai H, Hardell L. Cell Phone Radiofrequency Radiation Exposure and Brain Glucose Metabolism. JAMA: The Journal of the American Medical Association 2011;305(8):828-9. Cell Phone Radiofrequency Radiation Exposure and Brain Glucose Metabolism, February 23, 2011, Lai and Hardell 305 (8): 828 — JAMA

The results by Volkow et al1 add to the concern about possible acute and long-term health effects of radiofrequency emissions from wireless phones, including both mobile and cordless desktop phones. Although the biological significance, if any, of increased glucose metabolism from acute cell phone exposure is unknown, the results warrant further investigation. An important question is whether glucose metabolism in the brain would be chronically increased from regular use of a wireless phone with higher radiofrequency energy than those used in the current study. Potential acute and chronic health effects need to be clarified.

Much has to be done to further investigate and understand these effects. Do these effects occur from use of cell phones of different frequencies and waveforms? In a series of studies carried out in the 1980s, Sanders et al reported that the effect of radiofrequency radiation on energy metabolism in the rat brain was dependent on carrier frequency as well as pulse modulation frequency; ie, the wave characteristics of the radiofrequency radiation are important determinants of energy metabolism responses in brain tissues. Can the increase in glucose metabolism explain the increase in responsiveness in psychological tests observed in humans after exposure to cell phone radiation? Furthermore, an operating cell phone also generates low frequency and extremely low frequency electromagnetic fields. The biological effects of these fields emitted by cell phones have received little attention. However, many studies have indicated that these fields, at much lower frequency than the radiofrequency field, are biologically active. Can these fields also affect neural tissue metabolism?

Could the findings of Volkow et al be a marker of other alterations in brain function from radiofrequency emissions, such as neurotransmitter and neurochemical activities? If so, this might have effects on other organs leading to unwanted physiological responses. Further studies on biomarkers of functional brain changes from exposure to radiofrequency radiation are definitely warranted.

 

[Michael Scally MD]

Schematic illustration of the interactions of between homeostatic/ metabolic and hedonic control of food intake in normal weight and obese individuals. Palatable foods reinforce their consumption by increasing both the motivational and hedonic components of the reward process. Whereas homeostatic signals are able to put a brake on food reinforcement in normal weight individuals, this does not appear to be the case for the obese. Moreover, increased food intake in obesity may reflect an allostatic shift in the set-point for food reward, characterized by either an increased hedonic requirement (the reward hyperfunction theory) or an increased motivation to compensate for a hedonic deficit (the reward hypofunction theory). By analogy with chemical drug addiction, problematic over-eating may commence with an increased hedonic requirement but with increased exposure, the hedonic/rewarding value of the food decreases, resulting in an increased motivation for food (ie eating in the absence of pleasure in the ‘food addicted’ state). Unfortunately obesity- associated leptin and insulin resistance likely play an important role to desynchronize these appetitive brain mechanisms. Recent studies have identified the central ghrelin signalling system as having an important role for increasing food reward. Given that obese individuals appear to remain ghrelin sensitive, future therapies for problematic overeating could include ghrelin antagonists.


Egecioglu E, Skibicka KP, Hansson C, et al. Hedonic and incentive signals for body weight control. Rev Endocr Metab Disord. http://www.springerlink.com/content/81v260408wvq0l22/fulltext.pdf

Here we review the emerging neurobiological understanding of the role of the brain's reward system in the regulation of body weight in health and in disease. Common obesity is characterized by the over-consumption of palatable/rewarding foods, reflecting an imbalance in the relative importance of hedonic versus homeostatic signals. The popular 'incentive salience theory' of food reward recognises not only a hedonic/pleasure component ('liking') but also an incentive motivation component ('wanting' or 'reward-seeking'). Central to the neurobiology of the reward mechanism is the mesoaccumbal dopamine system that confers incentive motivation not only for natural rewards such as food but also by artificial rewards (eg. addictive drugs). Indeed, this mesoaccumbal dopamine system receives and integrates information about the incentive (rewarding) value of foods with information about metabolic status. Problematic over-eating likely reflects a changing balance in the control exerted by hypothalamic versus reward circuits and/or it could reflect an allostatic shift in the hedonic set point for food reward. Certainly, for obesity to prevail, metabolic satiety signals such as leptin and insulin fail to regain control of appetitive brain networks, including those involved in food reward. On the other hand, metabolic control could reflect increased signalling by the stomach-derived orexigenic hormone, ghrelin. We have shown that ghrelin activates the mesoaccumbal dopamine system and that central ghrelin signalling is required for reward from both chemical drugs (eg alcohol) and also from palatable food. Future therapies for problematic over-eating and obesity may include drugs that interfere with incentive motivation, such as ghrelin antagonists.

 

[Michael Scally MD]

The aim of the present study was to critically assess the available literature in order to evaluate the available evidence for treatments of elderly patients with growth hormone deficiency (GHD).


Kokshoorn N, Biermasz NR, Roelfsema F, Smit JW, Pereira AM, Romijn JA. Growth hormone replacement therapy in elderly growth hormone deficient patients: a systematic review. Eur J Endocrinol. http://www.eje-online.org/cgi/reprint/EJE-10-1170v1.pdf

Context: Recombinant human growth hormone (rhGH) is indicated for the treatment of adults with growth hormone deficiency (GHD). However, conflicting data are available on the efficacy of rhGH treatment in elderly GHD patients.

Objective: To assess the efficacy of rhGH treatment in elderly GHD subjects

Methods: We searched PubMed, Cochrane Library, Web of Science, and EMBASE.

Study selection: Eligible studies included GHD patients, aged >60 years, treated by rhGH.

Data extraction was performed by two reviewers independently.

Results: We found 11 eligible studies with a total of 534 patients. Only 2 studies had prospective, randomized, placebo-controlled study designs with a duration of rhGH treatment of 6 (n=15) and 12 months (n=62), respectively. Treatment with rhGH decreased total and LDL cholesterol levels by 4-8% and 11-16%, respectively, but did not alter HDL or triglyceride levels. RhGH did not affect body mass index, but decreased waist circumference (by~3cm) and waist/hip ratio. RhGh did not consistently affect blood pressure or bone mineral density. RhGH increased lean body mass by 2-5% and decreased total fat mass by 7-10% in 4 studies, but did not affect body composition in 2 other studies. RhGH consistently improved quality of life (QoL) parameters reflected in AGHDA-scores. There are no explicit data on elderly GHD patients aged >80 yrs.

Conclusion: RhGH replacement in elderly subjects with GHD decreases LDL cholesterol levels and improves QoL, but the effects on other parameters are not unequivocal. There are no data on the efficacy and safety of rhGH treatment in octogenarians with GHD.