Life Extension Magazine®

Issue: May 2015

Zinc, DHEA, Cholesterol, and Folate

Zinc, DHEA, Cholesterol, and Folate

By Life Extension.

Zinc transporters in prostate cancer.

Prostate cancer is a major health concern as it has the second highest incidence rate among cancers in men. Despite progress in tumor diagnostics and therapeutic approaches, prognosis for men with advanced disease remains poor. In this review we provide insight into the changes of the intermediary metabolism in normal prostate and prostate cancer. In contrast to normal cells, prostate cancer cells are reprogrammed for optimal energy-efficiency with a functional Krebs cycle and minimal apoptosis rates. A key element in this relationship is the uniquely high zinc level of normal prostate epithelial cells. Zinc is transported by the SLC30 and SLC39 families of zinc transporters. However, in prostate cancer the intracellular zinc content is remarkably reduced and expression levels of certain zinc transporters are altered. Here, we summarize the role of different zinc transporters in the development of prostate cancer.

Mol Aspects Med. 2013 Apr-Jun;34(2-3):735-41

Zinc and its transporters, pancreatic- cells, and insulin metabolism.

Zinc is an essential trace metal for life. Two families of zinc transporters, SLC30A (ZNT) and SLC39A (ZIP) are required for maintaining cellular zinc homeostasis. ZNTs function to decrease cytoplasmic zinc concentrations whereas ZIPs do the opposite. Expression of zinc transporters can be tissue/cell-type specific or ubiquitous. Zinc transporters that are limited in tissue/cell distributions usually perform specialized tasks to satisfy biological processes in a given cell. For example, ZNT8 is mainly expressed in b-cells and functions to deliver zinc into granules for insulin maturation and secretion. Many other zinc transporters are also expressed in b-cells. Defects in these zinc transporters have been associated with abnormalities in insulin synthesis, maturation, and secretion and subsequent glucose metabolism. This review focuses on the specific roles of zinc and its transporters in insulin metabolism and describes the current knowledge of the function of zinc transporters in b-cell health in animal knockout mouse models with respect to diabetes development in humans.

Vitam Horm. 2014;95:365-90

Zinc and zinc transporters in normal prostate and the pathogenesis of prostate cancer.

Zinc is an essential metal for all cells. It plays a role in a wide variety of physiological and biochemical processes. In the prostate epithelial cell the accumulation of high cellular zinc is a specialized function that is necessary for these cells to carry out the major physiological functions of production and secretion of citrate. The production of citrate and its secretion into prostatic fluid is a differentiated function of the prostate epithelial cells that is apparently important for reproduction. The loss of citrate and zinc accumulation is the most consistent and persistent characteristic of prostate malignancy. This characteristic of prostate cancer indicates that the lost ability of the malignant cells to accumulate zinc and citrate is an important factor in the development and progression of malignancy. The lost ability of the epithelial cells to accumulate zinc and thus to also accumulate citrate is the result of decreased expression of specific zinc uptake transporters. The purpose of this presentation is to review the current understanding of zinc and zinc homeostasis in the prostate and the role of zinc and zinc transporters in the normal function of the prostate and the pathogenesis of prostate cancer.

Front Biosci. 2005 Sep 1;10:2230-9

Zinc in the human prostate gland: normal, hyperplastic and cancerous.

Zinc concentration in a prostate gland is much higher than in other human tissues. Data for zinc changes in different prostate diseases are limited and greatly contradictory. To analyze transrectal puncture tissue biopsy and resected materials, zinc content was estimated in benign prostatic hyperplasia (BPH) and cancer. There were 109 patients studied (50 BPH and 59 cancer). The control group consisted of 37 intact glands of men who died an unexpected death (accident, murder, acute cardiac insufficiency, etc.). All materials studied were divided into two parts. One of them was morphologically examined, while the zinc content of another one was estimated. The radionuclide induced energy dispersive X-ray fluorescent analysis was used for zinc determination. Zinc content (M +/- SE) of normal prostate, BPH and cancer was 1018 +/- 124, 1142 +/- 77, and 146 +/- 10 micrograms/g dry tissue, respectively. It was shown that zinc assessment in the material of transrectal puncture biopsy of prostate indurated site can be used as an additional test for differential diagnosis of BPH and cancer. Accuracy, sensitivity and specificity of the test are 98 +/- 2%.

Int Urol Nephrol. 1997;29(5):565-74

A Critical Assessment of Epidemiology Studies Regarding Dietary/Supplemental Zinc and Prostate Cancer Risk.

Despite the prevalence of prostate cancer, the etiology and factors associated with its development and progression are largely unknown. An important relationship in prostate cancer is the role of zinc. Clinical evidence and experimental evidence have established that prostate cancer is associated with a decrease in the zinc uptake and accumulation in the malignant cells; and that the accumulation of zinc in the prostate cells prevents malignancy. In contrast to this established consistent clinical relationship, numerous epidemiology studies and reports of the effect of dietary and supplemental zinc on the incidence of prostate cancer have provided divergent, inconsistent, and inconclusive results; which range from adverse effects of zinc, protective effects of zinc, and no effect of zinc on the risk of prostate cancer. Despite these divergent and inconclusive results, a prevailing view and public warning has evolved from unsubstantiated and uncorroborated epidemiology studies that zinc consumption increases the risk of developing advanced stage prostate cancer. Such a conclusion is not well-founded and has serious, confusing and erroneous implications for the medical/scientific community and for the public-at-large. The admonition of Dimitrios Trichopoulos over a decade ago [1] that, “ … (epidemiology) studies will inevitably generate false positive and false negative results with disturbing frequency. …, when (people) do take us seriously, we may unintentionally do more harm than good ” can be applied to the situation that is the subject of this report. Therefore it is extremely important to review the epidemiology studies that have lead to the conclusion of an adverse effect of zinc, and also that have produced such inconsistent and divergent results. This critical review defines issues, problems, and shortcomings that exist in the conduct, conclusions, and dissemination of the epidemiology studies. We caution that one should be knowledgeable and understanding of these issues in assessing the validity and the conclusiveness of the outcomes from the epidemiology studies of purported associations of dietary and supplemental zinc on the risk of prostate cancer; particularly when the unsubstantiated conclusions are at odds with clinical and experimental evidence. It is in the interest of the medical, scientific and public communities that this critical review is undertaken. We hope that this review will generate an open, objective, scientific and medical discussion and assessment of this important issue.

Open Urol Nephrol J. 2008;1

Zinc as an anti-tumor agent in prostate cancer and in other cancers.

Human prostate glandular epithelial cells have the unique capability of accumulating high levels of zinc. This is essential to inhibit m-aconitase activity so that citrate can accumulate for secretion into prostatic fluid, which is a major function of the prostate gland. As a result, the Krebs cycle is truncated with the consequence of the lost ATP production that would result from citrate oxidation. The cellular accumulation of zinc also inhibits mitochondrial terminal oxidation and respiration. In addition to these metabolic effects, zinc accumulation exhibits anti-proliferative effects via its induction of mitochondrial apoptogenesis. Zinc accumulation also inhibits the invasive/migration activities in malignant prostate cells. The anti-proliferative effects and the effects on invasion and migration occur through zinc activation of specific intracellular signaling pathways. Consequently, these effects impose anti-tumor actions by zinc. The ability of prostate cells to accumulate zinc is due to the expression and activity of the zinc uptake transporter, ZIP1. To avoid the anti-tumor effects of zinc, in prostate cancer the malignant prostate cells exhibit a silencing of ZIP1 gene expression accompanied by a depletion of cellular zinc. Therefore we regard ZIP1 as a tumor suppressor gene in prostate cancer. In addition to prostate cells, similar tumor suppressor effects of zinc have been identified in several other types of tumors.

Arch Biochem Biophys. 2007 Jul 15;463(2):211-7

Serum zinc and prostate cancer risk in a nested case-control study: The multiethnic cohort.

BACKGROUND: Experimental studies have provided evidence that zinc has a protective effect against development and progression of prostate cancer. However, epidemiological studies have reported inconsistent findings. We evaluated the association between prediagnostic serum zinc and prostate cancer risk in a cohort of multiethnic population. METHODS: This case-control study is nested within the Multiethnic Cohort of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites in Hawaii and California. The analysis included 392 prostate cancer cases and 783 controls matched on age, race/ethnicity, date/time of blood draw and fasting status. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The mean serum zinc concentrations did not significantly differ between cases (94.9 µg/dl) and controls (93.9 µg/dl). No association was found between serum zinc levels and prostate cancer either overall or by tumor stage/grade. In ethnic-specific analyses, positive associations were found in Japanese Americans (OR for the highest vs. the lowest tertile = 2.59, 95% CI: 1.09-6.17) and Latinos (OR = 2.74, 95% CI: 1.05-7.10), whereas no association was observed in African Americans and whites. CONCLUSIONS: We found no evidence to support an inverse relationship between serum zinc and prostate cancer risk, and, to the contrary, found a suggestion in the ethnic-specific results of a possible increase in risk; however, blood concentrations of zinc may not adequately reflect the levels in prostate tissue. Further study with a larger sample size, and if possible, with assessment of zinc tissue levels, is warranted to confirm these findings

Prostate. 2013 Feb 15;73(3):261-6

Dietary zinc and prostate cancer in the TRAMP mouse model.

Circumstantial evidence indicates that zinc may have an important role in the prostate. Total zinc levels in the prostate are 10 times higher than in other soft tissues. Zinc concentrations in prostate epithethial cancer cells are decreased significantly. Zinc supplementation for prevention and treatment of prostate cancer in humans has yielded controversial results. No studies have been reported in animal models to show the effect of zinc supplementation on prevention of prostate cancer, thus far. In this study, we have examined the effect of zinc supplementation on development of prostate cancer in a TRAMP mouse model. Results from our study indicate that dietary zinc plays an important role in prostate carcinogenesis. Tumor weights were significantly higher when the dietary zinc intake was either deficient or high in comparison to normal zinc intake level, suggesting that an optimal dietary zinc intake may play a protective role against prostate cancer. Further, our studies also showed decreased insulin-like growth factor (IGF)-1 and IGF-1/IGF binding protein-3 ratio in normal zinc-supplemented animals, suggesting that zinc may modulate IGF-1 metabolism in relation to carcinogenesis. We conclude that optimal prostate zinc concentration has a protective role against cancer.

J Med Food. 2010 Feb;13(1):70-6

The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots.

BACKGROUND: The genetic and molecular mechanisms responsible for and associated specifically with the development and progression of malignant prostate cells are largely unidentified. In addition, despite its implication in virtually all malignant cells, the role of altered cellular metabolism as an essential factor in prostate malignancy has been largely ignored. Moreover, the intermediary metabolism of normal prostate as well as malignant prostate cells is among the least studied and most poorly understood of all mammalian cells. Some important factors, especially the role of zinc, have been identified and implicated in the development and progression of prostate malignancy. In this review, we provide a current and updated integrated assessment of the relationships of intermediary metabolism in normal prostate and in prostate cancer. The experimental and clinical evidence that leads to the formulation of concepts of normal and malignant prostate metabolism is presented. The evidence for a concept of zinc as a tumor suppressor agent and Zip1 zinc transporter as a tumor-suppressor gene is described. RESULTS: The specialized function of the normal prostate glandular epithelium to produce and secrete enormously high levels of citrate involves and requires unique intermediary metabolism activities that are not generally associated with other normal mammalian cells. The accumulation of zinc by these cells is an essential factor in this unique metabolic relationship. In malignancy, the normal zinc-accumulating citrate-producing epithelial cells are metabolically transformed to citrate-oxidizing cells that lose the ability to accumulate zinc. A genetic alteration in the expression of ZIP1 zinc transporter is associated with this metabolic transformation. These genetic/metabolic relationships have important consequences on citrate-related metabolism, bioenergetics, cell proliferation and invasive capabilities of the malignant cells, which result in tumor-suppression characteristics. CONCLUSION: The genetic/metabolic relationships in normal prostate glandular epithelium are driven by the unique function to accumulate and secrete citrate. The genetic/metabolic transformation of the prostate malignant cells is driven by the metabolic/bioenergetic, growth/proliferative, and invasive/migration requirements of the malignant process. Zinc is critical to these relationships. An understanding of these genetic/metabolic relationships provides new directions and opportunities for development of regimens for the prevention and treatment of prostate cancer. Important insight into the genetic/metabolic requirements of the prostate malignant process is now evolving. Most importantly at this time, an appreciation and recognition of the genetic/metabolic significance and implications in the development of prostate malignancy is imperative; and much needed research in this area is essential. Hopefully, this review will help to achieve these goals.

Mol Cancer. 2006 May 15;5:17

Semenogelin, the predominant protein in human semen. Primary structure and identification of closely related proteins in the male accessory sex glands and on the spermatozoa.

The predominant protein in human semen, semenogelin, was characterized by lambda gt11 clones isolated from a seminal vesicular cDNA library. One clone, carrying a cDNA insert of 1606 nucleotides and a polyadenylated tail, coded for the entire semenogelin precursor. An open reading frame of 1386 nucleotides encodes a signal peptide and the mature protein of 439 amino acid residues, in which residues 85-136 are identical with a previously characterized semenogelin fragment. The polypeptide chain displays a most conspicuous region of internal sequence homology where 46 of the 58 amino acid residues at positions 259-316 are repeated at positions 319-376. An abundant seminal vesicular transcript of 1.8 kilobases (kb) codes for semenogelin. Two additional transcripts, one seminal vesicular 2.2-kb species and one epididymal 2.0-kb species, code for related proteins that have a close structural relationship as well as antigenic epitopes in common with semenogelin. Semenogelin and the semenogelin-related proteins are the major proteins involved in the gelatinous entrapment of ejaculated spermatozoa. Antigenic epitopes common to these proteins are localized to the parts of the spermatozoa involved in locomotion. The spermatozoa become progressively motile as the gel-forming proteins are fragmented by the kallikrein-like protease, prostate-specific antigen, and the gel dissolves.

J Biol Chem. 1989 Jan 25;264(3):1894-900

The pH of prostatic fluid: a reappraisal and therapeutic implications.

A basic assumption in all experiments on prostatic physiology, particularly those designed to study the diffusion of drugs into the prostate gland, is that the pH of human prostatic fluid is similar to that of the dog, that is pH 6.1 to 6.5. We believe that this assumption is incorrect. Our data indicate 1) the expressed prostatic secretion of most normal men is alkaline (mean pH 7.31), 2) with prostatic infection the pH of prostatic fluid increases markedly (mean pH 8.34) and, therefore, drugs shown to diffuse into the canine prostate may be ineffective in treating prostatitis in humans and 3) the increase in pH of the expressed prostatic secretion seen with infection is not simply owing to an increase in the relative concentration of alkaline seminal vesicular components. Biochemical markers of seminal vesicular activity (fructose and prostaglandins) showed no correlation with pH values of expressed prostatic secretion. Hence, it appears that the change in pH of the expressed secretion is owing to a real increase in pH of prostatic fluid. The clinical implications of these findings are discussed. An appreciation of the profound variation in the prostatic fluid pH may be of importance not only in furthering the understanding and treatment of chronic bacterial prostatitis but, also, of other prostatic diseases as well.

J Urol. 1978 Dec;120(6):695-8

Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity.

A major issue relating to many cancers is the absence of effective chemotherapeutic agents; so that most often untreatable morbidity and death are prevalent once the cancer has been detected and has advanced. The search for efficacious anticancer agents is imperative. One potential agent is zinc, which is decreased in the development of some cancers in order to avoid its cytotoxic/tumor suppressor effects on the malignant cells. This provides the basis and opportunity to employ a treatment regimen that restores elevated zinc levels in the malignant cells and elicits the cytotoxic/tumor suppressor effects of zinc. The enigma is that this approach and expectation has not reached fruition. The question is “why?”. This article provides a discussion of relevant zinc issues that need to be considered and resolved. Important areas of research are identified as being essential for the successful application of zinc cytotoxicity/tumor suppression actions for the treatment of specific cancers.

Expert Rev Anticancer Ther. 2012 Jan;12(1):121-8

Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause.

The adrenal production of the delta 5-androgens, dehydroepiandrosterone (DHEA) and its sulfate ester dehydroepiandrosterone sulfate (DHEAS), declines linearly with aging. The evidence that DHEA or DHEAS administration may alleviate some of the problems related to aging has opened new perspectives for clinical research. The present study aims to investigate the effects of a 6-month DHEA supplementation in early and late postmenopausal women, with normal or overweight body mass index (BMI), on the level of circulating steroids, sex hormone binding globulin (SHBG), beta-endorphin and gonadotropins, and on the adrenal gland response to dexamethasone suppression and adrenocorticotropic hormone (ACTH) stimulation. Early postmenopausal women (50-55 years) both normal weight (BMI 20-24, n = 9) and overweight (BMI 26-30, n = 9) and late postmenopausal women (60-65 years) both of normal weight and overweight, were treated with oral DHEA (50 mg/day). Circulating DHEA, DHEAS, 17-OH pregnenolone, progesterone, 17-OH progesterone, allopregnenolone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, SHBG, cortisol, luteinizing hormone, follicle stimulating hormone and beta-endorphin levels were evaluated monthly and a Kupperman score was performed. The product/precursor ratios of adrenal steroid levels were used to assess the relative activities of the adrenal cortex enzymes. Before and after 3 and 6 months of therapy, each women underwent an ACTH stimulating test (10 micrograms i.v. in bolus) after dexamethasone administration (0.5 mg p.o.) to evaluate the response of cortisol, DHEA, DHEAS, androstenedione, 17-OH pregnenolone, allopregnanolone, progesterone and 17-OH progesterone. The between-group differences observed before treatment disappeared during DHEA administration. Levels of 17-OH pregnenolone remained constant during the 6 months. Levels of DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone increased progressively from the first month of treatment. Levels of estradiol and estrone significantly increased after the first/second month of treatment. Levels of SHBG significantly decreased from the second month of treatment only in overweight late postmenopausal women, while the other groups showed constant levels. Progesterone levels remained constant in all groups, while 17-OH progesterone levels showed a slight but significant increase in all groups. Allopregnanolone and plasma beta-endorphin levels increased progressively and significantly in the four groups, reaching values three times higher than baseline. Levels of cortisol and gonadotropins progressively decreased in all groups. The product/precursor ratios of adrenal steroid levels at the sixth month were used to assess the relative activities of the adrenal cortex enzymes and were compared to those found before therapy. The 17,20-desmolase, sulfatase and/or sulfotransferase, 17,20-lyase and 5 alpha-reductase activities significantly increased, while the 3 beta-hydroxysteroid-oxidoreductase activity did not vary. On the contrary, the 11-hydroxylase and/or 21-hydroxylase activities showed a significant decrease after 6 months of treatment. In basal conditions, dexamethasone significantly suppressed all the adrenal steroids and this suppression was greater after 3 and 6 months of treatment for DHEA, DHEAS and allopregnanolone, while it remained unchanged for other steroids. Before treatment, ACTH stimulus induced a significant response in all parameters; after the treatment, it prompted a greater response in delta 5- and delta 4-androgens, progesterone and 17-OH progesterone, while cortisol responded less in both younger and older normal-weight women. The endometrial thickness did not show significant modifications in any of the groups of postmenopausal women during the 6 months of treatment. Treatment with DHEA was associated with a progressive improvement of the Kupperman score in all groups, with major effects on the vasomotor symptoms in

Gynecol Endocrinol. 2000 Oct;14(5):342-63

Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men.

Dehydroepiandrosterone sulfate (DS) was measured by direct tritium RIA in longitudinal plasma specimens from 97 normal healthy male participants in the Baltimore Longitudinal Study of Aging. Fasting blood was collected at regular visits (approximately 1.5 yr apart) over an average 13 yr of adulthood (cumulative age range: 32-83 yr). DS was measured in 3-4 widely spaced specimens from each subject. A decline in DS was found in 65 (67%) subjects, 13 subjects (13%) showed no change, and increases were found in the 19 remaining subjects during the study period. A plot of individual data points revealed the same pattern we had obtained previously from a cross-sectional study of a different normal male population. A plot of DS values vs. age among subjects whose DS increased during the study also revealed an age-related decline. Thus, the longitudinal decrease in circulating DS, long inferred from cross-sectional data, is confirmed for normal men in the present study. A more detailed study of every specimen collected during the study period from 12 of the Baltimore Longitudinal Study of Aging subjects (4 whose values tended to be low, 4 whose values tended to be high, and 4 whose values were near the mean) failed to reveal any patterns of variation that could be correlated with changes in life circumstances, health status, or any other discernible factors. Hence, the wide variability seen in DS among individuals within normal populations remains unexplained.

J Clin Endocrinol Metab. 1992 Oct;75(4):1002-4

Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging.

The present data show a dramatic decline in the circulating levels of dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), androst-5-ene-3 beta,17 beta-diol (5-diol), 5-diol-sulfate, 5-diol-fatty acid esters, and androstenedione in both men and women between the ages of 20-80 yr. In the 50- to 60-yr-old group, serum DHEA decreased by 74% and 70% from its peak values in 20- to 30-yr-old men and women, respectively. the serum concentrations of the conjugated metabolites of dihydrotestosterone (DHT), namely androsterone (ADT)-G, androstane-3 alpha,17 beta-diol (3 alpha-diol-G), androstane-3 beta,17 beta-diol (3 beta-diol-G), and ADT-sulfate are the most reliable parameters of the total androgen pool in both men and women, whereas serum testosterone and DHT can be used as markers of testicular secretion in men and interstitial ovarian secretion in women. The serum concentration of these various conjugated androgen metabolites decreased by 40.8% to 72.8% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in men and women, respectively, thus suggesting a parallel decrease in the total androgen pool with age. As estimated by measurement of the circulating levels of these conjugated metabolites of DHT, it is noteworthy that women produce approximately 66% of the total androgens found in men. In women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues, whereas in men the testes and DHEA and DHEA-S provide approximately equal amounts of androgens at the age of 50-60 yr. An additional potentially highly significant observation is that the majority of the marked decline in circulating adrenal C19 steroids and their resulting androgen metabolites takes place between the age groups of 20- to 30-yr olds and 50- to 60-yr-olds, with smaller changes are observed after the age of 60 yr.

J Clin Endocrinol Metab. 1997 Aug;82(8):2396-402

Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood.

In a cross-sectional study, serum dehydroepiandrosterone sulfate (DS) concentrations were measured in 981 men and 481 women, aged 11-89, yr. The resulting data were asymetrically distributed and were normalized by logarithmic transformation and analyzed by 5-yr age grouping (e.g. 15-19 yr, 20-24 yr, etc.). The DS concentration peaked at age 20-24 yr in men (logarithmic mean, 3470 ng/ml) and at age 15-19 yr in women (log mean, 2470 ng/ml). Mean values then declined steadily in both sexes (log mean at greater than 70 yr of age, 670 ng/ml in men and 450 ng/ml in women) and were significantly higher in men than women at ages from 20-69 yr. Analysis of 517 randomly selected sera (from women) which had been stored frozen for 10-15 yr gave results indistinguishable from values obtained from fresh specimens. In a supplementary study, a longitudinal analysis of weekly specimens from 4 normal men, aged 36-59 yr, revealed individual variability (mean coefficient of variation, 19%) and failed to demonstrate any monthly, seasonal, or annual rhythmicity. Based on the above analyses, a table of normal serum DS ranges for adult men and women is presented for use as a clinical reference.

J Clin Endocrinol Metab. 1984 Sep;59(3):551-5

DHEA enhances effects of weight training on muscle mass and strength in elderly women and men.

The plasma levels of dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) decline approximately 80% between the ages of 25 and 75 yr. Muscle mass and strength also decrease with aging. Published data on the effects of DHEA replacement on muscle mass and strength are conflicting. The goals of this study were to determine whether DHEA replacement increases muscle mass and strength and/or enhances the effects of heavy resistance exercise in elderly women and men. We conducted a randomized, double-blind, placebo-controlled study of the effects of 10 mo of DHEA replacement therapy with the addition of weightlifting exercise training during the last 4 mo of the study (DHEA + exercise group, n = 29; placebo + exercise group, n = 27). DHEA alone for 6 mo did not significantly increase strength or thigh muscle volume. However, DHEA therapy potentiated the effect of 4 mo of weightlifting training on muscle strength, evaluated by means of one-repetition maximum measurement and Cybex dynamometry, and on thigh muscle volume, measured by magnetic resonance imaging. Serum insulin-like growth factor concentration increased in response to DHEA replacement. This study provides evidence that DHEA replacement has the beneficial effect of enhancing the increases in muscle mass and strength induced by heavy resistance exercise in elderly individuals.

Am J Physiol Endocrinol Metab. 2006 Nov;291(5):E1003-8

Low serum levels of dehydroepiandrosterone sulfate predict all-cause and cardiovascular mortality in elderly Swedish men.

CONTEXT: The age-related decline in dehydroepiandrosterone (DHEA) levels is thought to be of importance for general and vascular aging. However, data on the association between DHEA and mortality are conflicting. OBJECTIVES: We tested the hypothesis that low serum DHEA and DHEA sulfate (DHEA-S) levels predict all-cause and cardiovascular disease (CVD) death in elderly men. DESIGN, SETTING, AND PARTICIPANTS: We used gas/liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based MrOS Sweden study (2644 men, aged 69-81 yr). Mortality data were obtained from central registers and analyzed using Cox proportional hazards regressions. MAIN OUTCOME MEASURES: All-cause and CVD mortality by serum DHEA(-S) levels. RESULTS: During a mean 4.5-yr follow-up, 328 deaths occurred. Low levels of DHEA-S (quartile 1 vs. quartiles 2-4), predicted death from all causes [hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.21-1.96; adjusted for traditional cardiovascular risk factors], from CVD (n = 123 deaths; HR 1.61, 95% CI 1.10-2.37) and ischemic heart disease (n = 73; HR 1.67, 95% CI 1.02-2.74) but not cancer. Analyses with DHEA gave similar results. The association between low DHEA-S and CVD death remained after adjustment for C-reactive protein and circulating estradiol and testosterone levels. When stratified by the median age of 75.4 yr, the mortality prediction by low DHEA-S was more pronounced among younger (age adjusted HR for CVD death 2.64, 95% CI 1.37-5.09) than older men (HR 1.30, 95% CI 0.83-2.04). CONCLUSIONS: Low serum levels of DHEA(-S) predict death from all causes, CVD, and ischemic heart disease in older men.

J Clin Endocrinol Metab. 2010 Sep;95(9):4406-14.

Age-related decline in salivary dehydroepiandrosterone sulfate and associated health risks among African Americans.

OBJECTIVES: Dehydroepian-drosterone sulfate (DHEAS) declines with age and low endogenous DHEAS concentrations have been associated with obesity. In addition, DHEAS has been studied for its role in mood and wellbeing. However, limited data are available on salivary DHEAS concentrations in African Americans. Thus, we examined age-related changes in morning salivary DHEAS and the association between DHEAS and obesity risk factors among African Americans. DESIGN: Salivary DHEAS samples (n=170) were obtained from men and women divided into three age groups: 18 to 30 (young), 31 to 45 (middle) and 46 to 60 (older) years. Anthropometric, blood glucose, high sensitivity c-reactive protein (hsCRP), and blood pressure measures were obtained. Participants completed the Center for Epidemiologic Studies Depression (CESD), Beck Depression Inventory (BDI), Daily Hassles Scale (DHS), Perceived Stress Scale (PSS) and Pittsburgh Sleep Quality Index (PSQI) scales to assess depression, daily hassles, stress and quality of sleep, respectively. RESULTS: Mean salivary DHEAS concentrations decreased significantly with increasing age: mean values were 25.8 +/- 2.4, 21.9 +/- 1.9, and 14.4 +/- .9 nmol/L for young, middle, and older groups, respectively. Like DHEAS, PSQI, DHS, CESD, MAP, WC, BMI, systolic and diastolic BP and fasting blood glucose values differed significantly in the older compared to the young and middle groups. Women had significantly lower salivary DHEAS than men (P< or =.05). CONCLUSION: The age-related decline in salivary DHEAS in African Americans is associated with cardiovascular risk factors, sleep quality, hassles and mood. Whether supplementing DHEAS levels in aging African Americans will improve health remains to be determined.

Ethn Dis. 2013 Spring;23(2):149-54

Dehydroepiandrosterone and its sulfate predict the 5-year risk of coronary heart disease events in elderly men.

BACKGROUND: The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory. OBJECTIVES: This study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men. METHODS: We used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers. RESULTS: During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality. CONCLUSIONS: Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

J Am Coll Cardiol. 2014 Oct 28;64(17):1801-10

Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women.

BACKGROUND AND PURPOSE: Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk of ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic-related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance. METHODS: Between 1989 and 1990, 32,826 women without prior stroke in the Nurses’ Health Study, an observational cohort, provided blood samples and were followed up for cardiovascular events. Among this sample, using a nested case-control design, 461 ischemic strokes were confirmed by medical records by 2006. Cases were matched to controls free of stroke at the time of the index case and by age, race, menopausal status, postmenopausal hormone use, smoking status, and date of sample collection. Multivariable conditional logistic regression was used. RESULTS: Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0; P=0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk of 1.30 for ischemic stroke (95% confidence interval, 0.88-1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (relative risk=1.33; 95% confidence interval, 0.87-2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (≤the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared with those with higher levels (relative risk=1.41; 95% confidence interval, 1.03-1.92). CONCLUSIONS: Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.

Stroke. 2013 Jul;44(7):1784-9

Role of DHEA in cardiovascular diseases.

Dehydroepiandrosterone (DHEA) is a steroid hormone derived from cholesterol synthesized by the adrenal glands. DHEA and its 3b-sulphate ester (DHEA-S) are the most abundant circulating steroid hormones. In human, there is a clear age-related decline in serum DHEA and DHEA-S and this has suggested that a relative deficiency in these steroids may be causally related to the development of a series of diseases associated with aging including cardiovascular diseases (CVD). This commentary aims to highlight the action of DHEA in CVD and its beneficial effect in therapy. We thus discuss the possible impact of serum DHEA decline and DHEA supplementation in diseases such as hypertension, coronary artery disease and atherosclerosis. More specifically, we provide evidence for a beneficial action of DHEA in the main disease of the pulmonary circulation: pulmonary hypertension. We also examine the potential cellular mechanism of action of DHEA in terms of receptors (membrane/nuclear) and associated signaling pathways (ion channels, calcium signaling, PI3K/AKT/eNos pathway, cGMP, RhoA/RhoK pathway). We show that DHEA acts as an anti-remodeling and vasorelaxant drug. Since it is a well-tolerated and inexpensive drug, DHEA may prove to be a valuable molecule in CVD but it deserves further studies both at the molecular level and in large clinical trials.

Biochem Pharmacol. 2013 Mar 15;85(6):718-26

Associated hormonal declines in aging: DHEAS.

DHEA and its sulfate prohormone DHEAS are the most abundant circulating adrenal steroid hormones in humans. DHEA exerts its actions on peripheral target tissues either indirectly, following its conversion to androgens, estrogens or both, or directly, as a steroid hormone interacting with either a nuclear or a membrane receptor. In humans, DHEA shows a characteristic pattern of secretion throughout life. Serum DHEA concentrations decline with advancing age and vary with gender, ethnicity, and environmental factors. Epidemiological studies show an inverse relationship between plasma DHEA(S) levels in men and age-related illnesses, including cardiovascular and metabolic diseases, immune disorders, malignancies, and neurological dysfunction. This has generated great interest on the putative role of DHEA in age-associated illnesses. Administration of DHEA to rats and mice reduces visceral fat accumulation, and improves insulin resistance in experimental models of diet-induced obesity and/or Type 2 diabetes. In addition, recent studies in vitro have shown that DHEA has the capacity to improve endothelial function by increasing nitric oxide (NO) synthesis. Replacement of DHEA in patients with adrenal insufficiency has been shown to exert beneficial effects on well-being, mood, and sexuality. By contrast, in healthy individuals, the physiological age-associated decline in circulating DHEA(S) per se does not justify DHEA supplementation, since the effects of this hormone on metabolic abnormalities, endothelial function in vivo, and cardiovascular events are contradictory. However, these results do not exclude the possibility that DHEA treatment may prove beneficial in specific subgroups of elderly subjects.

J Endocrinol Invest. 2005;28(3 Suppl):85-93

Activation of immune function by dehydroepiandrosterone (DHEA) in age-advanced men.

BACKGROUND: Substantial data from animal studies have demonstrated a stimulatory effect of dehydroepiandrosterone (DHEA) on immune function. However, little is known about the effects of DHEA on the human immune system. Since aging is associated with a decline in immune function and in DHEA production, we proposed that oral administration of DHEA to elderly men would result in activation of their immune system. METHODS: Nine healthy age-advanced men (mean age of 63 years) with low DHEA-sulfate levels participated in this study. They were treated nightly with an oral placebo for 2 weeks followed by DHEA (50 mg) for 20 weeks. Fasting (0800h-0900h) blood samples were obtained at 4- to 8-week intervals for immune function studies and hormone determinations. Freshly isolated peripheral lymphocytes were used for flow cytometric identification of lymphocyte subsets, cells expressing the IL-2 receptor (IL-2R), mitogen stimulation studies, and for determining natural killer (NK) cell number and cytotoxicity. Levels of interleukin-2 (IL-2) and IL-6 secreted from cultured lymphocytes were determined under basal and mitogen stimulated conditions. Sera were analyzed for soluble IL-2 Receptor (sIL-2R) levels, insulin-like growth factor-I (IGF-I) and IGF binding protein-I (IGFBP-I) concentrations. RESULTS: Baseline levels of serum DHEA sulfate (DHEAS), a stable marker of circulating DHEA levels, were 2 standard deviations below young adult values and increased 3-4 fold within 2 weeks. These levels were sustained throughout the duration of DHEA administration. When compared with placebo, DHEA administration resulted in a 20% increase (p < .01) in serum IGF-I, a decreasing trend in IGFBP-I, and a 32% increase in the ratio of IGF-I/IGFBP-I (p < .01). Activation of immune function occurred within 2-20 weeks of DHEA treatment. The number of monocytes increased significantly (p < .01) after 2 (45%) and 20 (35%) weeks of treatment. The population of B cells fluctuated with increases (p < .05) at 2 (35%) and 10 (29%) weeks of treatment. B cell mitogenic response increased 62% (p < .05) by 12 weeks unaccompanied by changes in serum IgG, IgA, and IgM levels. Total T cells and T cell subsets were unaltered. However, a 40% increase (p < .05) in T cell mitogenic response, 39% increase in cells expressing the IL-2R (CD25+) (p < .05), and 20% increase in serum sIL-2R levels (p < .01) were found at 12-20 weeks of DHEA treatment, suggesting a functional activation of T lymphocytes occurred. In vitro mitogen stimulated release of IL-2 and IL-6 was enhanced 50% (p < .05) and 30% (p < .01) respectively by 20 weeks of treatment without basal secretion being affected. NK cell number showed a 22-37% increase (p < .01) by 18-20 weeks of treatment with a concomitant 45% increase (p < .01) in cytotoxicity. There were no adverse effects noted with DHEA administration. CONCLUSION: Administration of oral DHEA at a daily dose of 50 mg to age-advanced men with low serum DHEAS levels significantly activated immune function. The mechanism(s) to account for the immunoenhancing properties of DHEA are unclear. Consideration is given to the potential role of an increase in bioavailable IGF-I, which by virtue of its mitogenic effects on immune cell function, may mediate the DHEA effects. While extended studies are required, our findings suggest potential therapeutic benefits of DHEA in immunodeficient states.

J Gerontol A Biol Sci Med Sci. 1997 Jan;52(1):M1-7

Cardiovascular disease is associated with greater incident dehydroepiandrosterone sulfate decline in the oldest old: the
cardiovascular health study all stars study.

OBJECTIVES: To describe cross-sectional and longitudinal associations with dehydroepiandrosterone sulfate (DHEAS) and change in DHEAS with age. DESIGN: Longitudinal cohort study. SETTING: Pittsburgh, Pennsylvania. PARTICIPANTS: Cardiovascular Health Study All Stars study participants assessed in 2005/06 (N=989, mean age 85.2, 63.5% women, 16.5% African American). MEASUREMENTS: Health characteristics were assessed in 2005/06 according to DHEAS level, mean DHEAS and DHEAS change across age categories were tested, and linear and logistic regression was used to identify factors present in 1996/97 associated with continuous and categorical DHEAS change. RESULTS: Mean +/- standard deviation DHEAS was 0.555 +/- 0.414 microg/mL in 1996/97 and 0.482 +/- 0.449 microg/mL in 2005/06 for women and 0.845 +/- 0.520 microg/mL in 1996/97 and 0.658 +/- 0.516 microg/mL in 2005/06 for men. In 2005/06, DHEAS was lower in women and subjects with cardiovascular disease (CVD) and chronic pulmonary disease and higher for African Americans and subjects with hypertension and high cholesterol. Mean DHEAS change was greater in men (-0.200 microg/mL) than in women (-0.078 microg/mL) (P<.001). Each 1-year increase in age attenuated the effect of male sex by 0.01 microg/mL (P=.009), abolishing the sex difference in DHEAS change by age 79. Presence of CVD before the study period was associated with greater absolute DHEAS change (beta=-0.04 microg/mL, P=.04) and with the fourth quartile of DHEAS change versus the first to third quartiles (odds ratio=1.46, 95% confidence interval=1.03-2.05). CONCLUSION: DHEAS change continues into very old age, is not homogenous, is affected by sex, and is associated with prevalent CVD. Future studies should investigate factors that might accelerate DHEAS decline.

J Am Geriatr Soc. 2010 Mar;58(3):421-6

Application of new cholesterol guidelines to a population-based sample.

BACKGROUND: The 2013 guidelines of the American College of Cardiology and the American Heart Association (ACC-AHA) for the treatment of cholesterol expand the indications for statin therapy for the prevention of cardiovascular disease. METHODS: Using data from the National Health and Nutrition Examination Surveys of 2005 to 2010, we estimated the number, and summarized the risk-factor profile, of persons for whom statin therapy would be recommended (i.e., eligible persons) under the new ACC-AHA guidelines, as compared with the guidelines of the Third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program, and extrapolated the results to a population of 115.4 million U.S. adults between the ages of 40 and 75 years. RESULTS: As compared with the ATP-III guidelines, the new guidelines would increase the number of U.S. adults receiving or eligible for statin therapy from 43.2 million (37.5%) to 56.0 million (48.6%). Most of this increase in numbers (10.4 million of 12.8 million) would occur among adults without cardiovascular disease. Among adults between the ages of 60 and 75 years without cardiovascular disease who are not receiving statin therapy, the percentage who would be eligible for such therapy would increase from 30.4% to 87.4% among men and from 21.2% to 53.6% among women. This effect would be driven largely by an increased number of adults who would be classified solely on the basis of their 10-year risk of a cardiovascular event. Those who would be newly eligible for statin therapy include more men than women and persons with a higher blood pressure but a markedly lower level of low-density lipoprotein cholesterol. As compared with the ATP-III guidelines, the new guidelines would recommend statin therapy for more adults who would be expected to have future cardiovascular events (higher sensitivity) but would also include many adults who would not have future events (lower specificity). CONCLUSIONS: The new ACC-AHA guidelines for the management of cholesterol would increase the number of adults who would be eligible for statin therapy by 12.8 million, with the increase seen mostly among older adults without cardiovascular disease.

N Engl J Med. 2014 Apr 10;370(15):1422-31

Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions.

Numerous large-scale clinical studies have revealed that the low-density lipoprotein cholesterol (LDL-C)-lowering effect of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) prevents coronary heart disease (CHD). Statins have not only LDL-C-lowering effects but also high-density lipoprotein cholesterol (HDL-C)-elevating effects, which differ among statins. In this article, we discuss the molecular mechanisms of HDL-C elevation by statins and its effect on HDL functions. We summarize the reports to date on the effects of statins on various proteins, enzymes and receptors involved in reverse cholesterol transport (RCT), which is one of the protective systems against atherosclerosis. Since statins increase the synthesis of apolipoprotein A-I (ApoA-I) and HDL neogenesis in the liver, the HDL-C-increasing effect of statins may reflect RCT activation. Moreover, HDL has pleiotropic effects, including anti-inflammatory and anti-oxidative effects, as well as RCT. In the future, it may be necessary to assess the functions of HDL elevated by statins, and select statins based on differences in their effects in clinical practice.

J Atheroscler Thromb. 2010 May;17(5):436-51

Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database.

The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL-C were positively related to statin dose with rosuvastatin and simvastatin but inversely related to dose with atorvastatin. There was no apparent relationship between reduction in LDL-C and increase in HDL-C, whether analyzed overall for all statins (correlation coefficient = 0.005) or for each statin individually. Percentage increase in apolipoprotein A-I was virtually identical to that of HDL-C at all doses of the three statins. Baseline concentrations of HDL-C and triglyceride (TG) and presence of diabetes were strong, independent predictors of statin-induced elevations of HDL-C. Statins vary in their HDL-C raising ability. The HDL-C increase achieved by all three statins was independent of LDL-C decrease. However, baseline HDL-C and TGs and the presence of diabetes were predictors of statin-induced increases in HDL-C.

J Lipid Res. 2010 Jun;51(6):1546-53

Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue,
autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder.

INTRODUCTION: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a medical illness characterized by disorders in inflammatory and oxidative and nitrosative (IO&NS) pathways. METHODS: This paper examines the role of Coenzyme Q10 (CoQ10), a mitochondrial nutrient which acts as an essential cofactor for the production of ATP in mitochondria and which displays significant antioxidant activities. Plasma CoQ10 has been assayed in 58 patients with ME/CFS and in 22 normal controls; the relationships between CoQ10 and the severity of ME/CFS as measured by means of the FibroFatigue (FF) scale were measured. RESULTS: Plasma CoQ10 was significantly (p=0.00001) lower in ME/CFS patients than in normal controls. Up to 44.8% of patients with ME/CFS had values beneath the lowest plasma CoQ10 value detected in the normal controls, i.e. 490 microg/L. In ME/CFS, there were significant and inverse relationships between CoQ10 and the total score on the FF scale, fatigue and autonomic symptoms. Patients with very low CoQ10 (<390 microg/L) suffered significantly more from concentration and memory disturbances. DISCUSSION: The results show that lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion. Our results suggest that patients with ME/CFS would benefit from CoQ10 supplementation in order to normalize the low CoQ10 syndrome and the IO&NS disorders. The findings that lower CoQ10 is an independent predictor of chronic heart failure (CHF) and mortality due to CHF may explain previous reports that the mean age of ME/CFS patients dying from CHF is 25 years younger than the age of those dying from CHF in the general population. Since statins significantly decrease plasma CoQ10, ME/CFS should be regarded as a relative contraindication for treatment with statins without CoQ10 supplementation.

Neuro Endocrinol Lett. 2009;30(4):470-6

Coenzyme Q10: an independent predictor of mortality in chronic heart failure.

OBJECTIVES: The aim of this study was to investigate the relationship between plasma coenzyme Q(10) (CoQ(10)) and survival in patients with chronic heart failure (CHF). BACKGROUND: Patients with CHF have low plasma concentrations of CoQ(10), an essential cofactor for mitochondrial electron transport and myocardial energy supply. Additionally, low plasma total cholesterol (TC) concentrations have been associated with higher mortality in heart failure. Plasma CoQ(10) is closely associated with low-density lipoprotein cholesterol (LDL-C), which might contribute to this association. Therefore we tested the hypothesis that plasma CoQ(10) is a predictor of total mortality in CHF and could explain this association. METHODS: Plasma samples from 236 patients admitted to the hospital with CHF, with a median (range) duration of follow-up of 2.69 (0.12 to 5.75) years, were assayed for LDL-C, TC, and total CoQ(10). RESULTS: Median age at admission was 77 years. Median (range) CoQ(10) concentration was 0.68 (0.18 to 1.75) micromol/l. The optimal CoQ(10) concentration for prediction of mortality (established with receiver-operator characteristic [ROC] curves) was 0.73 micromol/l. Multivariable analysis allowing for effects of standard predictors of survival--including age at admission, gender, previous myocardial infarction, N-terminal peptide of B-type natriuretic peptide, and estimated glomerular filtration rate (modification of diet in renal disease)--indicated CoQ(10) was an independent predictor of survival, whether dichotomized at the ROC curve cut-point (hazard ratio [HR]: 2.0; 95% confidence interval [CI]: 1.2 to 3.3) or the median (HR: 1.6; 95% CI: 1.0 to 2.6). CONCLUSIONS: Plasma CoQ(10) concentration was an independent predictor of mortality in this cohort. The CoQ(10) deficiency might be detrimental to the long-term prognosis of CHF, and there is a rationale for controlled intervention studies with CoQ(10).

J Am Coll Cardiol. 2008 Oct 28;52(18):1435-41

Beneficial effects of artichoke leaf extract supplementation on increasing HDL-cholesterol in subjects with primary mild hypercholesterolaemia: a double-blind, randomized, placebo-controlled trial.

The aim of this study was to evaluate the effects of artichoke leaf extract (ALE) supplementation (250 mg, 2 b.i.d.) on the lipid pattern. A randomized, double-blind, placebo-controlled clinical trial was performed on 92 overweight subjects with primary mild hypercholesterolaemia for 8 weeks. Forty-six subjects were randomized to supplementation (age: 54.2 ± 6.6 years, body mass index (BMI): 25.8 ± 3.9 kg/m(2), male/female: 20/26) and 46 subjects to placebo (age: 53.8 ± 9.0 years, BMI: 24.8 ± 1.6 kg/m(2), male/female: 21/25). Verum supplementation was associated with a significant increase in mean high-density lipoprotein (HDL)-cholesterol (p < 0.001) and in mean change in HDL-cholesterol (HDL-C) (p = 0.004). A significantly decreased difference was also found for the mean change in total cholesterol (p = 0.033), low-density lipoprotein (LDL)-cholesterol (p < 0.001), total cholesterol/HDL ratio (p < 0.001) and LDL/HDL ratio (p < 0.001), when verum and placebo treatment were compared. These results indicate that ALE could play a relevant role in the management of mild hypercholesterolaemia, favouring in particular the increase in HDL-C, besides decreasing total cholesterol and LDL-cholesterol.

Int J Food Sci Nutr. 2013 Feb;64(1):7-15

Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation.

High serum concentration of low-density lipoprotein cholesterol (LDL-C) is a major risk factor for coronary heart disease. The efficacy of pantethine treatment on cardiovascular risk markers was investigated in a randomized, triple-blinded, placebo-controlled study, in a low to moderate cardiovascular disease (CVD) risk North American population eligible for statin therapy, using the National Cholesterol Education Program (NCEP) guidelines. A total of 32 subjects were randomized to pantethine (600 mg/day from weeks 1 to 8 and 900 mg/day from weeks 9 to 16) or placebo. Compared with placebo, the participants on pantethine showed a significant decrease in total cholesterol at 16 weeks (P=0.040) and LDL-C at 8 and 16 weeks (P=0.020 and P=0.006, respectively), and decreasing trends in non-high-density lipoprotein cholesterol at week 8 and week 12 (P=0.102 and P=0.145, respectively) that reached significance by week 16 (P=0.042). An 11% decrease in LDL-C from baseline was seen in participants on pantethine, at weeks 4, 8, 12, and 16, while participants on placebo showed a 3% increase at week 16. This decrease was significant between groups at weeks 8 (P=0.027) and 16 (P=0.010). The homocysteine levels for both groups did not change significantly from baseline to week 16. Coenzyme Q10 significantly increased from baseline to week 4 and remained elevated until week 16, in both the pantethine and placebo groups. After 16 weeks, the participants on placebo did not show significant improvement in any CVD risk end points. This study confirms that pantethine lowers cardiovascular risk markers in low to moderate CVD risk participants eligible for statins according to NCEP guidelines.

Vasc Health Risk Manag. 2014 Feb 27;10:89-100

Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia.

HMG-CoA reductase inhibitors (statins) are the mainstay in the pharmacologic management of dyslipidemia. Since they are widely prescribed, their safety remains an issue of concern. Rosuvastatin has been proven to be efficacious in improving serum lipid profiles. Recently published data from the JUPITER study confirmed the efficacy of this statin in primary prevention for older patients with multiple risk factors and evidence of inflammation. Rosuvastatin exhibits high hydrophilicity and hepatoselectivity, as well as low systemic bioavailability, while undergoing minimal metabolism via the cytochrome P450 system. Therefore, rosuvastatin has an interesting pharmacokinetic profile that is different from that of other statins. However, it remains to be established whether this may translate into a better safety profile and fewer drug-drug interactions for this statin compared with others. Herein, we review evidence with regard to the safety of this statin as well as its interactions with agents commonly prescribed in the clinical setting. As with other statins, rosuvastatin treatment is associated with relatively low rates of severe myopathy, rhabdomyolysis, and renal failure. Asymptomatic liver enzyme elevations occur with rosuvastatin at a similarly low incidence as with other statins. Rosuvastatin treatment has also been associated with adverse effects related to the gastrointestinal tract and central nervous system, which are also commonly observed with many other drugs. Proteinuria induced by rosuvastatin is likely to be associated with a statin-provoked inhibition of low-molecular-weight protein reabsorption by the renal tubules. Higher doses of rosuvastatin have been associated with cases of renal failure. Also, the co-administration of rosuvastatin with drugs that increase rosuvastatin blood levels may be deleterious for the kidney. Furthermore, rhabdomyolysis, considered a class effect of statins, is known to involve renal damage. Concerns have been raised by findings from the JUPITER study suggesting that rosuvastatin may slightly increase the incidence of physician-reported diabetes mellitus, as well as the levels of glycated hemoglobin in older patients with multiple risk factors and low-grade inflammation. Clinical trials proposed no increase in the incidence of neoplasias with rosuvastatin treatment compared with placebo. Drugs that antagonize organic anion transporter protein 1B1-mediated hepatic uptake of rosuvastatin are more likely to interact with this statin. Clinicians should be cautious when rosuvastatin is co-administered with vitamin K antagonists, cyclosporine (ciclosporin), gemfibrozil, and antiretroviral agents since a potential pharmacokinetic interaction with those drugs may increase the risk of toxicity. On the other hand, rosuvastatin combination treatment with fenofibrate, ezetimibe, omega-3-fatty acids, antifungal azoles, rifampin (rifampicin), or clopidogrel seems to be safe, as there is no evidence to support any pharmacokinetic or pharmacodynamic interaction of rosuvastatin with any of these drugs. Rosuvastatin therefore appears to be relatively safe and well tolerated, sharing the adverse effects that are considered class effects of statins. Practitioners of all medical practices should be alert when rosuvastatin is prescribed concomitantly with agents that may increase the risk of rosuvastatin-associated toxicity.

Am J Cardiovasc Drugs. 2010;10(1):11-28

Myopathy and rhabdomyolysis with lipid-lowering drugs.

Drug-induced myopathy and rhabdomyolysis are rare adverse drug reactions (ADR). They have been seen after the introduction of modern lipid-lowering drugs more regularly. The first description after medication with clofibrate dates back to 1968. Apparently, all fibrates can induce myopathy. It usually starts after a few days of medication, or after prolonged use, showing muscle weakness and/or pain. Concomitantly, the enzyme creatininephosphokinase (CPK) is raised dramatically. Muscular necrosis can follow leading secondarily to kidney failure, and eventually to death. For the class of statins, myopathy was more often seen after their introduction, and it became their most feared adverse effect, especially in combination of statins with other drugs (mibefradil, gemfibrozil, cyclosporin). In animal models the evolution of the disease and the mechanism of action may be elucidated. Though strong epidemiological data are lacking, the incidence of myopathy is probably similar for all lipid-lowering drugs and is in the range of 0.1-0.5% with monotherapy, increasing to 0.5-2.5% with combination therapy. Severe cases of rhabdomyolysis are rarer, but may have a significant mortality. The market success of cerivastatin within a short period has led to 100s of myopathies and some dozens of deaths. Though interactions on metabolism and ensuing high plasma levels can partially explain myopathy as intoxication, there are strong indications that other (endocrine, metabolic, genetic) factors might play a role in the pathophysiology. The patient population at risk should better be defined and withheld from myopathy-inducing drugs.

Toxicol Lett. 2002 Mar 10;128(1-3):159-68

Statin therapy and risk of developing type 2 diabetes: a meta-analysis.

OBJECTIVE: Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes. RESEARCH DESIGN AND METHODS: A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I(2) statistic. RESULTS: In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03-1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93-1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P = 0.03, I(2) = 57.7%). CONCLUSIONS: Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.

Diabetes Care. 2009 Oct;32(10):1924-9

Relationship between homocysteine and coronary artery disease. Results from a large prospective cohort study.

BACKGROUND: Coronary artery disease (CAD) still represents the major cause of mortality in developed countries. Large research programs have been focused on the identification of new risk factors to prevent CAD, with special attention to homocysteine (Hcy), due to the known associated increased thrombogenicity, oxidative stress status and endothelial dysfunction. However, controversy still exists on the association between Hcy and CAD. Therefore, aim of the current study was to investigate the association of Hcy with the prevalence and extent of CAD in a large consecutive cohort of patients undergoing coronary angiography. METHODS: Our population is represented by a total of 3056 consecutive patients undergoing coronary angiography between at the Azienda Ospedaliera “Maggiore della Carità”, Novara, Italy. Fasting samples were collected for homocysteine levels assessment. Coronary disease was defined for at least 1 vessel stenosis>50% as evaluated by QCA. RESULTS: Study population was divided according to Hcy tertiles (<13,3, 13,3-18.2, >18.2nmol/ml). High plasmatic level of homocysteine was related with age (p<0.001), male gender (p<0.001), hypertension (p<0.001) renal failure (p<0.001), family history of CAD (p<0.001), previous cerebrovascular accident (p<0.001), previous MI (p=0.002), previous CABG (p=0.003), ejection fraction (p<0.001), higher baseline creatinine (p<0.001), in treatment with nitrates (p<0.001), calcium antagonists (p<0.001), diuretics (p<0.001), Ace inhibitors (ACE-I) (p=0.006), Clopidogrel (p=0.05), haemoglobin (p=0.001), white blood cells (WBC) count (p=0.008), total cholesterol (p=0.04), Low-Density Lipoproteins (LDL) (p=0.01). A significant relationship was found between Hcy levels and the extent of coronary artery disease (71.8% vs 77.8% vs 77.4%, OR[95%CI]=1.18[1.11-1.252.], p<0.001 and severe CAD (23.6% vs 29.5% vs 32.1%, OR [95%CI]=1.275 [1.209-1.344], p<0.001). Elevated Hcy was significantly associated with increased risk of CAD (adjusted OR[95%CI]=1.087[1.009-1.171], p=0.02 and severe CAD (adjusted OR [95%CI]=1.07 [1.01-1.16, P=0.04]). The results were confirmed in the majority of high risk subsets of patients. CONCLUSIONS: This study showed that high levels of plasmatic Hcy are independently associated with CAD. Further large studies are certainly needed to explore the adjunctive benefits from vitamin administration in patients with elevated Hcy to prevent the occurrence and progression of CAD.

Thromb Res. 2014 Aug;134(2):288-93

The homocysteine controversy.

Mild to moderate hyperhomocysteinemia has been identified as a strong predictor of cardiovascular disease, independent from classical atherothrombotic risk factors. In the last decade, a number of large intervention trials using B vitamins have been performed and have shown no benefit of homocysteine-lowering therapy in high-risk patients. In addition, Mendelian randomization studies failed to convincingly demonstrate that a genetic polymorphism commonly associated with higher homocysteine levels (methylenetetrahydrofolate reductase 677 C>T) is a risk factor for cardiovascular disease. Together, these findings have cast doubt on the role of homocysteine in cardiovascular disease pathogenesis, and the homocysteine hypothesis has turned into a homocysteine controversy. In this review, we attempt to find solutions to this controversy. First, we explain that the Mendelian randomization analyses have limitations that preclude final conclusions. Second, several characteristics of intervention trials limit interpretation and generalizability of their results. Finally, the possibility that homocysteine lowering is in itself beneficial but is offset by adverse side effects of B vitamins on atherosclerosis deserves serious attention. As we explain, such side effects may relate to direct adverse effects of the B-vitamin regimen (in particular, the use of high-dose folic acid) or to proinflammatory and proproliferative effects of B vitamins on advanced

J Inherit Metab Dis. 2011 Feb;34(1):93-9

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 µg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

J Perinat Med. 2013 Sep 1;41(5):469-83

Does 5-methyltetrahydrofolate offer any advantage over folic acid?.

Almost half of the women do not follow the guidelines around folate suppletion before and during pregnancy, despite the proven benefit in the prevention of neural tube defects, miscarriages and premature births. The Belgian Superior Health Council recommends a minimum of 400 micrograms of folic acid or folate suppletion per day from 4 weeks before conception to 8 weeks thereafter. Many studies point to the importance of a wider intake period, more particularly at least 3 months before conception and throughout pregnancy and lactation. In high-risk women 4 mg is recommended until after the first 3 months of pregnancy. Afterwards the usual dose of 400 micrograms is sufficient. About half of the European population appears to have a gene mutation on the gene coding for the production of methylenetetrahydrofolate reductase, the enzyme that is involved in the formation of 5-methyltetrahydrofolate, which is, in his turn, responsible for the conversion of the toxic homocysteine in methionine. Women with such a gene polymorphism have a significantly higher risk to have a miscarriage or a baby with neural tube defects. For this reason, a search for an alternative form of synthetic folic acid supplement “pteroylmonoglutamic acid (PMG)” was conducted, particularly the calcium salt of 5-methyltetrahydrofolate (Metafolin). This offers the possibility to deliver the reduced folate immediately, which no longer needs to be converted by the reductase enzyme. Furthermore, this avoids free PMG in the circulation, lowers the risk for drug interactions and a vitamin B2 deficiency will not be masked. Despite clear guidelines regarding dietary supplements before and during pregnancy, their implementation is poor. Not only gynecologists but also GPs and pharmacists, should make more efforts to provide women of childbearing age with personal information. Especially risk groups such as adolescents, low-skilled or less well-off women and immigrants deserve special attention.

J Pharm Belg. 2012 Dec;(4):16-22

Folate metabolism and requirements.

Folate functions in multiple coenzyme forms in acceptance, redox processing and transfer of one-carbon units, including nucleotides and certain amino acids. Folate-requiring metabolic processes are influenced by folate intake, intake of other essential nutrients, including vitamins B-12 and B-6, and at least one common genetic polymorphism. Estimates of folate requirements have been based on intakes associated with maintenance of normal plasma and erythrocyte folate concentrations and functional tests that reflect abnormalities in folate-dependent reactions. Dietary Reference Intakes for folate that have been developed recently are based primarily on metabolic studies in which erythrocyte folate concentration was considered the major indicator of adequacy. For adults >/=19 y, the Recommended Dietary Allowance (RDA) is 400 microg/d of dietary folate equivalents (DFE); for lactating and pregnant women, the RDAs include an additional 100 and 200 microg of DFE/d, respectively.

J Nutr. 1999 Apr;129(4):779-82