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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
March 17, 2012

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Up All Night Eating? Here's Why
Insomnia Drugs Linked to Increased Mortality
Treatment of Alzheimer Disease: Stop, Add, or Switch?
Does Polycystic Ovary Syndrome Abate with Age?
Another Molecular Clue About Exercise's Power to Combat Obesity and Type 2 Diabetes
White Rice Postulated to Increase Diabetes Risk
PSA Testing Reduces Prostate Cancer Mortality, Follow-Up Study Shows
Study shows link in low levels of Vitamin D and depression symptoms
Vitamin D and Calcium Supplementation in Older Adults
GLP-1R Agonists (Byetta & Victoza) Associated with Weight Loss in Overweight Patients
Metformin Associated with Lower Cancer Risk
SSRIs During Pregnancy Slow Fetal Head Growth
Endometriosis Is Associated with Risk for Ovarian Carcinoma
Vitamin D Shrank Rats' Fibroids
Women’s Heart Risks Cut by Citrus and Cocoa

J Clin Endocrinol Metab 2012 Jan 18
Up All Night Eating? Here's Why
On seeing images of food, sleep-deprived men — regardless of their blood glucose levels — showed increased activation of a brain area involved in hunger motivation.
Sleep deprivation is associated with increased appetite and food intake — but why? Researchers in Europe have now explored this question, using functional magnetic resonance imaging to examine brain activations in response to images of low- and high-calorie food after a night of total sleep deprivation (TSD) and after 7 hours of sleep. The 12 participants (normal-weight men; mean age, 23) were used as their own controls, with sleep deprivation and normal sleep occurring in random order at least 2 weeks apart. A standardized dinner was provided before TSD or sleep; a standardized morning snack was provided before imaging.
Morning blood glucose levels were similar between the TSD and sleep conditions. However, the men reported significantly greater hunger after TSD, and they found 24% of the high-calorie food pictures (but none of the low-calorie ones) more appetizing after TSD than after a night's sleep. Compared with normal sleep, TSD was correlated with significantly greater activation of the right anterior cingulate cortex on seeing images of food.
Comment: The anterior cingulate cortex is involved in evaluating the potential reward from food and, through mesocorticolimbic connections, plays a role in hunger motivation. Independent of blood sugar, which can also influence appetite, sleep deprivation appears to activate this reward center, leading to greater reward from high-calorie foods — and, in turn, to calorie intake that overwhelms the somewhat increased energy expenditure that occurs with total sleep deprivation. Thus, people with chronic sleep deprivation may be more likely to overeat, and their preference for energy-dense foods may predispose them to weight gain and its complications.
Steven Dubovsky, MD Published in Journal Watch Psychiatry February 17, 2012
Citation(s):Benedict C et al. Acute sleep deprivation enhances the brain's response to hedonic food stimuli: An fMRI study. J Clin Endocrinol Metab 2012 Jan 18; [e-pub ahead of print]. (http://dx.doi.org/10.1210/jc.2011-2759)
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BMJ Open 2012 Feb 27; 2:e000850.
Insomnia Drugs Linked to Increased Mortality
But confounding could partly explain the findings in this observational study.
Hypnotic drugs, which many adults take for insomnia, have been associated with increased risks for cancer and death. Investigators clarified the extent of those risks by analyzing the medical records of 10,531 case patients (mean age, 54) who received prescriptions for hypnotic drugs and records of 23,674 matched controls who did not receive such prescriptions. Mortality data were acquired using the Social Security Death Index.
After a mean follow-up of 2.5 years, 6.1% of patients who received hypnotic drug prescriptions and 1.2% of patients who did not receive such prescriptions had died. Adjusted for multiple variables (e.g., age, tobacco use, body-mass index) and stratified by multiple comorbidities, the hazard ratios (HRs) for all-cause death were 3.6 for patients prescribed 1 to 18 doses yearly, 4.4 for patients prescribed 18 to 132 doses yearly, and 5.3 for patients prescribed >132 doses yearly compared with nonusers — a dose–response relation. The results were similar when the analysis was restricted to zolpidem (Ambien) or temazepam (Restoril), the most commonly prescribed hypnotic drugs. Patients who were prescribed >132 doses yearly of any hypnotic drug were also at significantly increased risk for cancer (HR, 1.4 compared with nonusers).
Comment: In this study, receiving a prescription for a hypnotic drug — even for ≤18 doses yearly — was associated with increased all-cause mortality risk, and receiving a prescription for many doses (>132 doses yearly) was associated with increased cancer risk. Given its design, this study does not prove that hypnotic drugs cause death or cancer. In addition, the authors were unable to control for psychiatric diagnoses such as depression or anxiety; therefore, residual confounding is possible. Nevertheless, the authors appropriately question the safety of these commonly prescribed drugs.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine March 13, 2012
Citation(s):Kripke DF et al. Hypnotics' association with mortality or cancer: A matched cohort study. BMJ Open 2012 Feb 27; 2:e000850. (http://dx.doi.org/10.1136/bmjopen-2012-000850
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N Engl J Med 2012 Mar 8; 366:893.
Treatment of Alzheimer Disease: Stop, Add, or Switch?
This randomized study finds little evidence of benefit from combining medications in patients with moderate-to-severe AD.
Pharmacotherapy for moderate-to-severe Alzheimer disease (AD) often starts with an acetylcholinesterase inhibitor and subsequently adds or substitutes memantine (Namenda®), the N-methyl-D-aspartate–receptor antagonist. Little controlled evidence exists on the effects of continuing, stopping, or switching medications. This double-blind, placebo-controlled study (planned sample size of 430 patients) enrolled 295 community-dwelling patients with moderate-to-severe AD (Mini-Mental State Examination [MMSE] scores, 5–13) who were already receiving donepezil 10 mg for at least 6 weeks. Donepezil was continued or discontinued (discontinuers received placebo) and augmented with memantine or placebo. Authors established "clinically relevant" changes at 52 weeks on the MMSE (change, 1.4 points) and the Bristol Activities of Daily Living Scale.
Although cognitive and functional status declined in all patients, deterioration differed among groups. Donepezil (Aricept®)continuers had better cognitive function (MMSE change, 1.9 points) and less functional impairment than donepezil discontinuers; these changes equaled 32% and 23%, respectively, of the deterioration in double-placebo recipients. Donepezil had a greater effect in moderate than in severe AD. Memantine recipients had better cognition and function than placebo recipients, but these differences were not clinically meaningful. Combining medications did not improve the benefit from donepezil.
Comment: The clinical question is whether slower deterioration in Alzheimer disease translates into a prolonged improved quality of life. These data suggest that the answer is yes for continuing donepezil for patients with moderate-to-severe AD. Combination therapy, frequently implemented in the U.S., showed no benefit. Memantine had a statistically, but not clinically, significant effect.
Other notable points: A larger study sample might have yielded additional differences. The findings may not pertain to patients with mild AD. Whether findings generalize to other acetylcholinesterase inhibitors is unclear. Memantine alone remains effective in persons who cannot take acetylcholinesterase inhibitors. Also, in an earlier study (JAMA 2004; 291:317), adjunctive memantine showed positive effects, which conflicts with the current results.
Jonathan Silver, MD Published in Journal Watch Psychiatry March 7, 2012
Citation(s):Howard R et al. Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med 2012 Mar 8; 366:893.
Schneider LS. Discontinuing donepezil or starting memantine for Alzheimer's disease.
N Engl J Med 2012 Mar 8; 366:957.
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Obstet Gynecol 2012 Feb; 119:263.
Does Polycystic Ovary Syndrome Abate with Age?
Some features of PCOS subsided during a 20-year follow-up.
To meet the well-established Rotterdam criteria for polycystic ovary syndrome (PCOS), a woman must exhibit two of these three characteristics: chronic anovulation, hyperandrogenism, and polycystic ovaries (with no evidence of other endocrine disease). Investigators assessed whether these and other features of PCOS change over time by following, for 20 years, 193 women in Italy with retrospectively diagnosed PCOS (mean age at diagnosis, 22). At diagnosis, 57% of the cohort had all three "classic" Rotterdam characteristics (phenotype A); 9% had no evidence of polycystic ovaries (phenotype B); 26% were ovulatory (phenotype C); and 7% had no evidence of hyperandrogenism (phenotype D). On average, the women with phenotype A were overweight, those with phenotype B were obese, and those in the other two groups were of normal weight.
Mean androgen levels (total testosterone and dehydroepiandrosterone sulfate) decreased over time; changes reached significance 10 years after diagnosis. Mean body-mass index (BMI) did not change significantly, but a significant increase in mean waist circumference was reached at 15 years. Mean insulin levels were significantly higher at baseline than in similarly aged healthy women with normal BMIs, and did not improve during follow-up. Ultrasound-determined ovarian volume was significantly lower at 20 years than at diagnosis, and the number of women with ovulatory cycles increased from 52 to 85 (18 of whom no longer met diagnostic criteria for PCOS). Of the 110 women who had all three PCOS characteristics at baseline, 38 (35%) no longer had all three traits at 20 years.
Comment: These data strongly suggest that women with characteristics of polycystic ovary syndrome experience improvement over the long term. However, it's not clear whether metabolic risks for cardiovascular disease and overt diabetes increase as women with persistent PCOS age; we must await further evidence to assess this common assumption.
Robert W. Rebar, MD Published in Journal Watch Women's Health February 23, 2012
Citation(s):Carmina E et al. A 20-year follow-up of young women with polycystic ovary syndrome. Obstet Gynecol 2012 Feb; 119:263.
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Nature 2012 Jan 26; 481:463
Another Molecular Clue About Exercise's Power to Combat Obesity and Type 2 Diabetes
Exercising muscle produces irisin, which converts calorie-storing white fat cells into calorie-burning brown fat cells.
During the past 14 years, researchers have identified an important biochemical pathway in energy metabolism. At the center of this pathway is a molecule called PGC1-α, a transcription factor that stimulates the coordinated activation of many other genes. Exercise triggers muscle cells to produce PGC1-α; as a result, white fat cells develop into brown fat cells (which burn rather than store calories; JW Gen Med Sep 30 2008), and insulin resistance is reduced. But how does muscle-derived PGC1-α elicit its effects in distant tissues?
These investigators now report that PGC1-α stimulates muscle cells to produce and secrete a hormone, which they call irisin. This hormone transforms subcutaneous white fat cells into brown fat cells. Even without exercise or decreases in caloric intake, irisin causes weight loss and reduced insulin resistance in mice. Human muscle also produces irisin in response to exercise; indeed, human and mouse irisin are identical.
Comment: These results demonstrate that exercise not only burns calories directly, but also causes the body to burn additional calories through activation of the PGC1-α pathway and subsequent production of irisin. Besides being an important discovery in the molecular physiology of exercise, irisin might one day constitute a treatment for obesity and insulin resistance. Many "silver bullets" for obesity have come and gone; still, I'd bet on this newly discovered molecule.
Anthony L. Komaroff, MD Published in Journal Watch General Medicine February 23, 2012
Citation(s):Boström P et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012 Jan 26; 481:463.
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White Rice Postulated to Increase Diabetes Risk
A meta-analysis finds increased risk for type 2 diabetes with high consumption of white rice. A comment in BMJ cautions against major dietary changes, however. (A brief interview with the senior author is available through the Clinical Conversations link below.)
Researchers examined the association between white rice consumption and diabetes risk in four observational studies comprising some 350,000 subjects; two thirds were from Western countries. Participants were free of self-reported diabetes at baseline and were followed for 4 to 22 years.
In comparisons between subjects in the highest and lowest consumption categories, the relative risk for diabetes was roughly 1.3 overall. Asian populations showed a significantly higher risk (1.55), whereas Western populations — with consumption levels roughly one fifth that of Asians — showed a 1.12 relative risk. The authors speculate that white rice's reduced nutrient content may play a role in the increased risk, in addition to its glycemic load.
An editorialist comments that the findings "cannot support large scale action."
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PSA Testing Reduces Prostate Cancer Mortality, Follow-Up Study Shows
Screening with prostate-specific antigen (PSA) testing reduces prostate cancer deaths, according to a follow-up report from the European Randomized Study of Screening for Prostate Cancer published in the New England Journal of Medicine. (The study's initial report, from 2009, yielded similar findings.)
The study included over 160,000 European men aged 55 to 69. The screening group was offered PSA testing (roughly every 4 years), while the controls were not. After a median 11 years' follow-up, prostate cancer mortality was reduced by 21% in the screening versus control group (absolute reduction, 1.07 deaths per 1000 men). Overall mortality did not differ between the groups.
The authors calculated that to prevent one prostate cancer death, 1055 men would need to be offered screening, and 37 cancers would need to be detected over 11 years.
They conclude: "More information on the balance of benefits and adverse effects, as well as the cost-effectiveness, of prostate-cancer screening is needed before general recommendations can be made."
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Study shows link in low levels of Vitamin D and depression symptoms
According to the UT Southwestern Medical Center psychiatrists that have worked together with the Cooper Center Longitudinal Study, low levels of vitamin D have been linked to depression. The study, published in Mayo Clinic Proceedings has helped in the clarification of the on going debate when smaller studies produced results that conflicted with the relationship between vitamin D and depression. This disorder classification affects almost 1-in-10 U.S. adults. UT Southwestern researchers examined the data from almost 12,600 participants from late in the year 2006 to late 2010. The results indicated that higher vitamin D levels were associated with significantly decreased risk of current depression, with particular note of those with a prior history of the disorder. Low vitamin D levels were associated with depressive symptoms, especially those with a history of depression. The study did not address whether there was a reduction in depressive symptoms with an in crease in vitamin D. Scientists have not yet been able to determine the exact relationship between vitamin D and depression nor how the interaction chemically occurs. Sherwood Brown, professor of psychiatry and senior author of the study done in conjunction with the Cooper Institute in Dallas indicated vitamin D may affect neurotransmitters, inflammatory markets and other factors, which could help explain the relationship with depression.
Vitamin D and Calcium linked to stomach fat reduction
A study involving 171 randomly assigned obese patients has uncovered some interesting results: Adding calcium and vitamin D to a regiment may reduce fat in the stomach area. It is known that vitamin D helps in the absorption of calcium for bone strength and that calcium is one of the most abundant minerals in the human body. Past studies have shown that diets that included a higher calcium density (higher levels of calcium per total calories) have been associated with a reduction in incidents of being overweight or general obesity. The patients in the study received regular or reduced calorie orange juice that was either fortified or unfortified with 350 mg of calcium and 100 international units of vitamin D per serving. Each group received three (3) 240 ml servings of the assigned orange juice every day for a period of 16 wks. Stomach fat tissue area was then measured before and after treatments. The results indicated that the average weight-loss of 2.45 kg was similar between the groups, however regardless of the calories, those that received the fortified orange juice had significantly greater reductions in stomach fat tissue than those receiving the unfortified orange juice. More research is required to completely understand the relationships between the calcium intake and body fat.
Those people at risk of Type 2 diabetes development may not seek lifestyle help
According to a new study published in the journal Diabetes Care, many patients that are at risk of developing Type 2 diabetes do not believe they require lifestyle counseling to assist in curbing their chances of developing the disease. The information was gathered from 10,149 patients that participated in the Finnish National Diabetes Prevention Project. The research by Sanna Salmela of the University of Jyvaskyla in Finland found that 52% of women and 36% of men believed they needed counseling. An additional finding is that those that agreed to attend supervised lifestyle assistance counseling were more likely to report a perceived need than those who agreed on their own self-initiated changes or those that refused to attend intervention at all. It appears that the need was directly associated with actual lifestyle intervention attendance only among the women.
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J Clin Endocrinol Metab 2012 Feb; 97:614
Vitamin D and Calcium Supplementation in Older Adults
A randomized trial found no effect on cancer or vascular mortality.
Intense interest surrounds the idea that vitamin D supplementation can prevent just about any disease under the sun (no pun intended). To address this issue, U.K. researchers present new findings from a previously published trial of vitamin D and calcium supplementation. Nearly 5300 patients (age, ≥70) with previous fractures were randomized to receive vitamin D3 (800 IU daily), calcium (1000 mg daily), both, or placebo. During 2 to 5 years of treatment, neither vitamin D nor calcium lowered rates of new fractures
(JW Gen Med Jun 10 2005).
Now, these researchers have examined nonfracture outcomes that occurred during the trial plus 3 more years of follow-up; the additional follow-up was added because clinically evident effects on cancer and cardiovascular disease might be delayed. During a median follow-up of 6 years, neither vitamin D nor calcium was associated with significantly higher or lower overall mortality, cancer mortality, cancer incidence, or vascular mortality (compared with placebo).
Comment: This study population was limited to elders with previous fractures, duration of treatment was only a few years, baseline serum 25-hydroxyvitamin D levels were low (about 15 ng/mL), and the 800-IU supplement increased serum levels by only about 10 ng/mL. However, vitamin D and calcium trials have been performed in various other populations; the authors review that literature and conclude that no decisive evidence yet exists to support a beneficial effect of vitamin D or calcium supplementation on vascular or cancer risk.
Allan S. Brett, MD Published in Journal Watch General Medicine March 13, 2012
Citation(s): Avenell A et al. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D3 and/or calcium (RECORD Trial). J Clin Endocrinol Metab 2012 Feb; 97:614. (http://dx.doi.org/10.1210/jc.2011-1309
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BMJ 2012 Jan 11; 344:d7771
GLP-1R Agonists (Byetta & Victoza) Associated with Weight Loss
in Overweight Patients

The association held for patients with or without diabetes.
In response to a meal, the intestine secretes glucagon-like peptide-1, which enhances insulin secretion, inhibits glucagon secretion, and suppresses appetite; evidence suggests that treatment with glucagon-like peptide-1 receptor (GLP-1R) agonists results in weight loss in patient with type 2 diabetes mellitus. Danish investigators conducted a meta-analysis to examine the weight-reducing effects of these agents.
Twenty-five randomized controlled trials (duration, 20–52 weeks) involving more than 6000 overweight and obese participants (mean body-mass index, 29–41) with or without type 2 diabetes were included. Participants received either a GLP-1R agonist (exenatide [Byetta] twice daily, extended-release exenatide [Bydureon] once weekly, or liraglutide [Victoza] once daily) or a control treatment (placebo, an oral hypoglycemic drug, or insulin). Participants receiving GLP-1R agonists experienced significantly greater weight loss than participants in the control groups (mean difference, 2.9 kg). Similar results were obtained for patients with or without diabetes. Finally, GLP-1R agonist use was associated with significantly reduced blood pressure and total cholesterol and with improved glycemic control.
Comment: Use of GLP-1R agonists results in weight loss, reduced blood pressure and total cholesterol, and improved glycemic control in overweight and obese patients with or without diabetes. Extended-release exenatide has recently received FDA approval for the treatment of type 2 diabetes; a clinical trial comparing extended-release exenatide to metformin and several other agents was recently published (JW Gen Med Feb 16 2012). Notably, most authorities would not regard these agents as first-line treatments for type 2 diabetes.
Paul S. Mueller, MD, MPH, FACP Published in Journal Watch General Medicine February 16, 2012
Citation(s):Vilsbøll T et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: Systematic review and meta-analyses of randomised controlled trials. BMJ 2012 Jan 11; 344:d7771. (http://dx.doi.org/10.1136/bmj.d7771)
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Diabetes Care 2012 Jan; 35:119
Metformin Associated with Lower Cancer Risk
Compared with sulfonylurea users (Glyburide/Glipizide), metformin users had a 10% lower incidence of cancer.
During the past decade, observational studies have suggested associations between cancer and type 2 diabetes (or insulin therapy). Although several plausible mechanisms exist (e.g., cancer cells express insulin receptors that when activated could promote cell proliferation in type 2 diabetic patients with hyperinsulinemia), the association remains controversial (CA Cancer J Clin 2010; 60:207). In some studies, metformin has been associated with decreased cancer risk.
In a population-based retrospective study, Dutch researchers recorded the incidence of cancer in 85,000 type 2 diabetic patients who initiated metformin or sulfonylurea monotherapy. During up to 10 years of follow-up, metformin users were less likely to receive cancer diagnoses than sulfonylurea users (hazard ratio, 0.9; 95% confidence interval, 0.88–0.91) after adjustment for age, sex, and several other variables. This 10% reduction was modest in relative terms but highly statistically significant. Metformin-associated lower risks were noted for cancers of the esophagus, stomach, colon, liver, pancreas, lung, breast, and prostate.
Comment: If hyperinsulinemia really does promote cancer, metformin theoretically could lower cancer risk in type 2 diabetic patients because it lowers circulating glucose and insulin levels in patients with insulin resistance and hyperinsulinemia. Unrecognized confounders could have affected the results of this study, but its intriguing results reinforce metformin as first-line therapy for type 2 diabetes.
Allan S. Brett, MD Published in Journal Watch General Medicine February 23, 2012
Citation(s):Ruiter R et al. Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: Results from a large population-based follow-up study. Diabetes Care 2012 Jan; 35:119. (http://dx.doi.org/10.2337/dc11-0857)
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Arch Gen Psychiatry 2012 Mar 5;
SSRIs During Pregnancy Slow Fetal Head Growth
Preterm birth was also associated with prenatal SSRI exposure.
Depression and exposure to selective serotonin reuptake inhibitors (SSRIs) during pregnancy have each been linked to adverse fetal and neonatal outcomes. In a population-based study, researchers prospectively examined fetal body and head growth and preterm birth in children of 99 mothers who used SSRIs (1.3% of the study population), 570 (7.4%) with clinically significant depressive symptoms but no SSRI use, and 7027 (91.3%) with no or low depressive symptoms and no SSRI exposure.
SSRI use during pregnancy was determined via self-reports and pharmacy records. Depressive symptoms were assessed with a questionnaire in mid-pregnancy. Fetal head-circumference and body growth was measured by ultrasonography in each trimester. Women in both depressed groups were more likely than controls to smoke and drink during pregnancy. SSRI users had significantly lower depressive-symptom scores than women with untreated depression.
Statistical analyses controlled for group differences in age, ethnicity, education, smoking, benzodiazepine use, and fetal sex. Untreated maternal depression was associated with reduced fetal body and head growth, but not with preterm birth. SSRI use was associated with an even more pronounced reduction in head growth, but not with slowed body growth. SSRI-exposed babies were more than twice as likely as controls to be born preterm (<37 weeks).
Comment: This study shows an association of SSRIs, over and above that of untreated depression, with a reduction in head-circumference growth, a prenatal marker of brain volume. The finding is concerning, given animal studies linking serotonin function with brain development (e.g., JW Psychiatry Dec 12 2011). This association study cannot establish a causal link. Still, clinicians treating pregnant women should reserve SSRIs for depression that is severe and unresponsive to alternative measures, such as psychotherapy. Other antidepressants, such as bupropion or mirtazapine, may be alternatives, but are less well studied during pregnancy than SSRIs.
Deborah Cowley, MD Published in Journal Watch Psychiatry March 12, 2012
Citation(s): El Marroun H et al. Maternal use of selective serotonin reuptake inhibitors, fetal growth, and risk of adverse birth outcomes. Arch Gen Psychiatry 2012 Mar 5; [e-pub ahead of print]. (http://dx.doi.org/10.1001/archgenpsychiatry.2011.2333
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Lancet Oncol 2012 Feb 22
Endometriosis Is Associated with Risk for Ovarian Carcinoma
Associations were documented for clear-cell, endometrioid, and low-grade serous ovarian cancer.
Although an association between endometriosis and invasive ovarian cancer has been suggested by several studies, the extent of the risk and any association with specific histologic subtypes have been unclear. In this study, data from 13 case-control studies from the U.S., Australia, and Europe were pooled to assess any associations.
In the analysis, 738 (9.3%) of 7911 women with invasive epithelial ovarian cancer and 168 (8.8%) with borderline ovarian cancer had a self-reported history of endometriosis. Of 13,226 controls without cancer, 818 (6.2%) reported such a history. Endometriosis was associated with a threefold increased risk for clear-cell ovarian cancer, a twofold increased risk for endometrioid carcinoma, and a twofold increased risk for low-grade serous ovarian cancer, after taking study site, age, ethnic origin, oral contraceptive use, and parity into account. No association was documented between endometriosis and invasive mucinous, serous high-grade ovarian cancer, or borderline tumors of any kind. Breast-feeding, weight, height, body-mass index, tubal ligation, and family history of ovarian cancer did not confound the associations.
Comment: Whereas associations between endometriosis and both clear-cell and endometrioid ovarian carcinoma have been reported previously, this is the first demonstration of an association between endometriosis and low-grade serous ovarian cancer. An editorialist notes that the first two associations might be explained by mutations in the ARID1A gene known to occur both in endometriotic tissue and in the two cancers, but the molecular basis of the association with low-grade serous carcinoma remains to be elucidated. The authors urge clinicians to be aware of the increased risk for specific subtypes of ovarian cancer in women with endometriosis; they suggest that, after further studies and with appropriate screening, it might be possible to identify subsets of women with endometriosis who are at increased risk for ovarian cancer.
Robert W. Rebar, MD Published in Journal Watch Women's Health March 15, 2012
Citation(s): Pearce CL et al. Association between endometriosis and risk of histological subtypes of ovarian cancer: A pooled analysis of case–control studies. Lancet Oncol 2012 Feb 22; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S1470-2045(11)70404-1)
Gourley C. Link between endometriosis and ovarian-cancer subtypes. Lancet Oncol 2012 Feb 22; [e-pub ahead of print]. (http://dx.doi.org/10.1016/S1470-2045(12)70029-3)
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Vitamin D Shrank Rats' Fibroids
Modest daily dose of vitamin D cut the size of rodents' uterine fibroids by 75 percent  
by Craig Weatherby
Three out of four women develop benign uterine fibroid tumors. While only some fibroids cause symptoms or need treatment, millions of women suffer their effects. Drugs may shrink the tumors, but effective, worry-free, non-surgical treatments have proven elusive. So it’s encouraging to hear that vitamin D shrank uterine fibroids in rats dramatically … albeit animals genetically predisposed to developing fibroids.

Although rats and people share much in biomedical terms, they don’t always react to nutrients and drugs the same way. Accordingly, the results of a new study concerning benign – but potentially painful, life-hindering – uterine fibroid tumors must be repeated in human trials. In prior research from Nashville’s Meharry Medical College, vitamin D inhibited the growth of human fibroid cells in the test tube. The new rodent experiment was funded by the National Institutes of Health (NIH) … and as Louis De Paolo, Ph.D., of NIH said, “[the outcomes] … provide a promising new lead in the search for a non-surgical treatment for fibroids ...” (NICHD 2012)

Uterine fibroids: a painful and costly burden
Uterine fibroids grow within and around the wall of the uterus, and are the most common non-cancerous tumors in women of childbearing age. Thirty percent of women 25 to 44 years of age report fibroid-related symptoms, such as lower back pain, heavy vaginal bleeding or painful menstrual periods. Uterine fibroids also are associated with infertility and such pregnancy complications as miscarriage or preterm labor.  Other than surgical removal of the uterus, there are few treatment options for women experiencing severe fibroid-related symptoms and about 200,000 U.S. women undergo the procedure each year. The National Institutes of Health (NIH) estimates that fibroid-related health expenses and lost productivity cost the United States from $6 billion to $34 billion annually (NICHD 2011). Fibroids are three to four times more common in African-American women than in white women. Moreover, African-American women are roughly 10 times more likely to be deficient in vitamin D than are white women.

Study finds vitamin D shrank rats’ fibroids by 75 percent
Scientists from Meharry Medical College conducted the research with colleagues from Vanderbilt University Medical Center … both located in Nashville.  The Nashville-based team tested vitamin D treatment on a strain of rats genetically predisposed to developing fibroid tumors (Halder SK et al. 2012). After examining the animals and confirming the presence of fibroids in 12 of them, the researchers divided the rats into two groups of six each:
Received intravenous vitamin D (test group)
No supplemental vitamin D provided (control group)

In the first group, small pumps implanted under the skin delivered a continuous dose of vitamin D for three weeks. The researchers then examined the animals in both groups, and found that fibroids shrunk dramatically in the rats receiving vitamin D. On average, uterine fibroids in the group receiving vitamin D were 75 percent smaller than those in the untreated group. In contrast, the tumors grew bigger in the untreated rats.

The amount of vitamin D the rats received each day was equivalent to a modest human dose … roughly 1,400 international units (IU). The recommended amount of vitamin D for teens and adults age 70 and under is 600 IU daily, although up to 4,000 units is considered safe for children over age nine, adults, and for pregnant and breastfeeding females (ODS 2011). According to co-author Ayman Al-Hendy, M.D., Ph.D., “Additional research is needed to confirm vitamin D as a potential treatment for women with uterine fibroids. But it is also an essential nutrient for the health of muscle, bone and the immune system, and it is important for everyone to receive an adequate amount of the vitamin.” (NICHD 2012)

Very few foods naturally contain vitamin D
As the NIH says, fatty fish such as wild salmon, mackerel, and tuna are the best natural sources of the vitamin (NICHD 2012). Fortified milk and other fortified foods provide small amounts of the vitamin (e.g., 100 IU per 8 oz of milk). Of course, vitamin D is also produced when ultraviolet rays from sunlight strike the skin. It’s important to note that light-skinned people make more vitamin D than dark-skinned people do from the same amount of sun exposure. This explains why vitamin D deficiency or inadequacy is more common among darker-skinned people.

 Sources: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Audio Briefing: Annual cost of fibroid tumors in the United States. December 23, 2011. Accessed at http://www.nichd.nih.gov/news/releases/122311-fibroid-economics.cfm. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Uterine Fibroids. February 19, 2007. Accessed at http://www.nichd.nih.gov/health/topics/Uterine_Fibroids.cfm Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Vitamin D shrinks fibroid tumors in rats. March 1, 2012. Accessed at http://www.nichd.nih.gov/news/releases/030112-vitaminD-fibroids.cfm Halder SK, Sharan C, Al-Hendy A. 1,25-Dihydroxyvitamin D3 Treatment Shrinks Uterine Leiomyoma Tumors in the Eker Rat Model. Biol Reprod. 2012 Feb 1. [Epub ahead of print]. DOI: 10.1095/biolreprod.111.098145. Mayo Clinic. Uterine fibroids. June 11, 2011. Accessed at
http://www.mayoclinic.com/health/uterine-fibroids/DS00078/DSECTION=treatments-and-drugs. Office of Dietary Supplements, U.S. National Institutes of Health (ODS). Dietary Supplement Fact Sheet: Vitamin D. June 24, 2011. Accessed at: http://ods.od.nih.gov/factsheets/VitaminD-QuickFacts/
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Women’s Heart Risks Cut by Citrus and Cocoa
UK study links that citrus fruits to reduce stroke risk in women; companion trial finds dark chocolate curbed heart risks in diabetic women. 
by Craig Weatherby
Most Americans fall far short of the intakes of fruits and vegetables advised by U.S. health agencies. Although some evidence suggests that diets higher in fruits and vegetables reduce cancer risks, the jury remains out. Instead, the USDA’s “Five-A- Day” campaign and similar ones rest primarily on evidence linking diets high in fruits and vegetables to lower risk of cardiovascular disease.

The cardiovascular benefits of fruits and vegetables – and their presumed but less certain anti-cancer effects – flow from these foods’ “antioxidant” polyphenol compounds … especially flavonoids. Population (epidemiological) studies consistently associate higher fruit, vegetable, and vitamin C intake with reduced stroke risk. Now the results of two studies – one clinical and one epidemiological – indicate cardiac benefits from foods rich in two sub-groups of flavonoids:

In January of this year, scientists from the UK’s University of East Anglia (UEA) reported that an antioxidant-enriched dark chocolate reduced cardiovascular risks among post-menopausal women with diabetes.  And last month, another UEA team reported that an epidemiological study linked diets high in flavanone-rich citrus fruits to a 19 percent drop in women’s stroke risk.

Citrus linked to re lower stroke risk among women
The University of East Anglia team collaborated with Harvard’s Eric Rimm, Sc.D., on a study in which they analyzed diet and health data collected from 69,622 women who took part in the 14-year-long Nurse’s Health Study (Cassidy A et al. 2012). The UEA-Harvard team looked for relationships between each of the six subclasses of flavonoids most abundant in western diets and risk of all stroke, whether hemorrhagic or ischemic (the most common kind by far, caused by blood clots). No significant associations were found between total flavonoid intake and stroke risk, probably because the physiological effects of the sub-classes differ. However, the women who reported eating the diets richest in flavanones (mostly from citrus fruits) were 19 percent less likely to suffer an ischemic stroke, compared with those estimated to consume the least flavanones.

It's not clear why the benefit was only seen in women, since most prior studies have not shown a big gender difference. As the researchers wrote, “… [this finding] fits with existing data on the protective effect of citrus fruit consumption.” (Cassidy A et al. 2012) Lead author Aedín Cassidy noted that flavonoids appear to stimulate or enhance several protective mechanisms, “… including improved blood vessel function and an anti-inflammatory effect.”

Dark chocolate deterred heart disease in diabetic women
A separate UEA team conducted a 12-month trial among 93 postmenopausal women with type 2 diabetes, whose ages ranged from 51 to 74 (Curtis PJ et al. 2012). Postmenopausal women with diabetes were chosen for the trial because they are a very high risk group for heart disease, even if they take statin drugs. The study was funded by Diabetes UK. The risk of death related to heart disease rises sharply after menopause, and having type 2 diabetes increases that risk by a whopping 350 percent (UEA 2012).

Prior studies indicate that dietary flavonoids reduce the risk factors for heart disease in healthy people. This trial was the first long-term study to examine their effect on a medicated, high-risk group. Half of the women ate two small bars of flavonoid-enriched chocolate daily, and half were given placebo chocolate bars. Importantly, women who were taking diabetes or heart drugs continued taking these medications during the trial and 10 years of follow-up. The chocolate bars used in the trial were enriched with more of the epicatechin-type flavanols naturally abundant in cocoa, and with certain of the isoflavone-class flavonoids found in soy beans.

The women in the test chocolate group were 3.4 percent less likely to suffer a heart attack in the next decade. This may sound like a small impact, but it would be considered a very substantial preventive effect for any “dietary intervention”. Better yet, their insulin resistance and cholesterol levels were significantly lower than the control (placebo chocolate) group. As Dr. Cassidy said, “These results are significant from a public health perspective because they provide further concrete evidence that diet has a beneficial clinical effect over and above conventional drug treatment.” (UEA 2012)

Chocolate and flavanols: Study authors sowed semantic confusion
Although the authors said that the test bars had more flavonoids than are found in “commercially available” bars, that is not accurate. The “test” chocolate bars given to half of the women contained 850mg of flavanols (including 90mg epicatechin) and 100mg of isoflavones (from soy). It’s not clear why the researchers chose to add isoflavones, and such a modest amount. Soy isoflavones do appear to benefit to arterial health, but cocoa flavanols have considerably more and better evidence in this regard. (Gil-Izquierdo A et al. 2011)

Vital Choice 80% Extra Dark Chocolate bars contain comparably high levels of flavanols: 3,192mg of epicatechin per 2 oz bar, or 782mg per one-half oz (one-quarter of a bar). In other words, just one-quarter bar of our chocolate provides more than eight times as much epicatechin as each of the test bars used in this trial.

How can we explain this discrepancy between the authors’ characterization of the test bars, and reality?

When the UEA team said “commercially available” chocolate, they probably meant milk chocolate (30% cocoa solids), which contains few flavanols. Even bars labeled “dark chocolate” may contain only 55% cocoa solids, and would have many fewer flavanols than an 80% cocoa bar like ours.

Sources: Bayard V, Chamorro F, Motta J, Hollenberg NK. Does flavanol intake influence mortality from nitric oxide-dependent processes? Ischemic heart disease, stroke, diabetes mellitus, and cancer in Panama. Int J Med Sci. 2007 Jan 27;4(1):53-8. Cano A, García-Pérez MA, Tarín JJ. Isoflavones and cardiovascular disease. Maturitas. 2010 Nov;67(3):219-26. Epub 2010 Aug 21. Review. Cassidy A, Rimm EB, O'Reilly EJ, Logroscino G, Kay C, Chiuve SE, Rexrode KM. Dietary Flavonoids and Risk of Stroke in Women. Stroke. 2012 Feb 23. [Epub ahead of print] doi: 10.1161/​STROKEAHA.111.637835. Accessed at http://stroke.ahajournals.org/content/early/2012/02/23/STROKEAHA.111.637835.abstract Chun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr. 2007 May;137(5):1244-52. Chun OK, Floegel A, Chung SJ, Chung CE, Song WO, Koo SI. Estimation of antioxidant intakes from diet and supplements in U.S. adults. J Nutr. 2010 Feb;140(2):317-24. Epub 2009 Dec 23. Erratum in: J Nutr. 2010 May;140(5):1062.  Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A. Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care. 2012 Feb;35(2):226-32. Epub 2012 Jan 16. Gil-Izquierdo A, Peñalvo LJ, Gil IJ, Medina S, Horcajada NM, Lafay S, Silberberg M, Llorach R, Zafrilla P, García-Mora P, Ferreres F. Soy Isoflavones and Cardiovascular Disease Epidemiological, clinical and -omics perspectives. Curr Pharm Biotechnol. 2011 Nov 25. [Epub ahead of print] Heiss C, Keen CL, Kelm M. Flavanols and cardiovascular disease prevention. Eur Heart J. 2010 Nov;31(21):2583-92. Epub 2010 Sep 18. Review. Hooper L, Kay C, Abdelhamid A, Kroon PA, Cohn JS, Rimm EB, Cassidy A. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2012 Mar;95(3):740-51. Epub 2012 Feb 1. Mursu J, Voutilainen S, Nurmi T, Tuomainen TP, Kurl S, Salonen JT. Flavonoid intake and the risk of ischaemic stroke and CVD mortality in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr. 2008 Oct;100(4):890-5. Epub 2008 Apr 1. Pase MP, Grima NA, Sarris J. The effects of dietary and nutrient interventions on arterial stiffness: a systematic review. Am J Clin Nutr. 2011 Feb;93(2):446-54. Epub 2010 Dec 8. Review. Shah ZA, Li RC, Ahmad AS, Kensler TW, Yamamoto M, Biswal S, Doré S. The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. J Cereb Blood Flow Metab. 2010 Dec;30(12):1951-61. Epub 2010 May 5. Siow RC, Mann GE. Dietary isoflavones and vascular protection: activation of cellular antioxidant defenses by SERMs or hormesis? Mol Aspects Med. 2010 Dec;31(6):468-77. Epub 2010 Sep 15. Review. Song WO, Chun OK. Tea is the major source of flavan-3-ol and flavonol in the U.S. diet. J Nutr. 2008 Aug;138(8):1543S-1547S. University of East Anglia (UEA). Diets high in flavonoids may reduce the risk of heart disease for women with type 2 diabetes, according to a new study by the University of East Anglia. January 16, 2012. Accessed at http://www.uea.ac.uk/mac/comm/media/press/2012/January/flavonoids-diabetes. Zamora-Ros R et al. Estimated dietary intakes of flavonols, flavanones and flavones in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24 hour dietary recall cohort. Br J Nutr. 2011 Dec;106(12):1915-25. Epub 2011 Jun 17.
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