OnLine First

[Michael Scally MD]

There are numerous published reports from the peer-reviewed literature each day. In order to help keep the Meso reader with the most up-to-date information this thread will provide breaking (within 30 days or less) research reports. If there is enough interest by posts for a certain report a separate thread will be considered. If one wishes to post to the thread breaking reports they must be within 30 days of the post date. Also, ALL posts as such MUST include a link to the original material. In most cases, this will be either the journal or PubMed. Do not link to secondary sources. If the full-text report is available, please provide. Often, writing to an author for the full-text is successful.

 

[Michael Scally MD]

The following report provides some insight into the controversy of hypothyroidism, particularly use of TSH alone.

Astapova I, Vella KR, Ramadoss P, et al. The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis. Mol Endocrinol:me.2010-0462. http://mend.endojournals.org/cgi/content/abstract/me.2010-0462v1 (The Nuclear Receptor Corepressor (NCoR) Controls Thyroid Hormone Sensitivity and the Set Point of the Hypothalamic-Pituitary-Thyroid Axis -- Astapova et al., 10.1210/me.2010-0462 -- Molecular Endocrinology)

The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoR{Delta}ID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T4 and T3 concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T4 and T3 and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic-pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell-specific TH action that would not be reflected by the serum TSH.

 

[Michael Scally MD]

In adults with GH deficiency, muscle mass is reduced with these differences reversed upon GH replacement. Androgen deficiency also results in a reduction in muscle mass, which is normalized by testosterone replacement. Thus, GH and testosterone both exert muscle anabolic effect and may act synergistically. Evidence shows that both hormones are necessary to exert an optimal effect. This is exemplified in GH-deficient men in whom lean body mass remains subnormal even after adequate androgen replacement. Linear growth in GH deficient children receiving GH replacement is further stimulated by androgen treatment, and for full androgen growth-promoting effect, GH replacement is required. This observation suggests that the anabolic effect of androgens may depend on the presence of GH. In prepubertal boys with GH deficiency, testosterone and GH replacement results in a greater stimulation of whole-body protein synthesis than testosterone treatment alone.

How GH and testosterone interact to regulate protein metabolism in adult life is poorly understood. Recently reported in hypopituitary men, both GH and testosterone promote protein anabolism, this effect being enhanced with combined treatment. Thus, testosterone and GH exert independent and additive effects in regulating protein metabolism. However, the primary site of GH and testosterone interaction is unknown. Liver and muscle are major sites where protein metabolism is regulated.

This study aimed to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. Oral delivery of testosterone exposes the liver to high portal levels of testosterone, which undergoes first-pass hepatic metabolism reducing or preventing the appearance of additional testosterone in the systemic circulation. This study compared the impact on whole-body protein metabolism of testosterone administered via oral route (at doses used resulting in solely hepatic testosterone exposure) with transdermal testosterone replacement (systemic testosterone exposure) in the presence or absence of GH.


Birzniece V, Meinhardt UJ, Umpleby MA, Handelsman DJ, Ho KKY. Interaction between Testosterone and Growth Hormone on Whole-Body Protein Anabolism Occurs in the Liver. J Clin Endocrinol Metab:jc.2010-521. http://jcem.endojournals.org/cgi/content/abstract/jc.2010-2521v1 (Interaction between Testosterone and Growth Hormone on Whole-Body Protein Anabolism Occurs in the Liver -- Birzniece et al., 10.1210/jc.2010-2521 -- Journal of Clinical Endocrinology & Metabolism)

Context - GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism.

Objective - Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic.

Design - In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared.

Patients and Intervention - Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation.

Main Outcome Measures - Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment.

Results - In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone.

Conclusion - In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction.

 

[Michael Scally MD]

Obesity and overweight have reached epidemic proportions in the U.S. and increasingly around the world. A number of studies have suggested that protein is the most satiating macronutrient and promotes the retention of lean body mass. Meals with increased protein to carbohydrate ratios have been demonstrated to increase satiety and decrease food intake by comparison to standard protein intake. Increased protein intake results in both improved weight loss and improved maintenance of weight loss. Therefore, protein enriched or supplemented meal replacements have found their way into weight management practice.

There has been some concern that the long-term use of high protein diets may damage liver function, renal function, or reduce bone density. While there are studies of the effects of increased intake of animal protein in the diet, protein-enriched meal replacements have not been evaluated in comparison to standard meal replacements in terms of effects on liver function, renal function, and bone mineral density in free-living populations.

Meal replacement (MR) is an important strategy in designing structured diets for weight management due to their simplicity, low cost, and convenience of protein-enriched meal replacement shakes by comparison to fast food meals. Meal replacements are as effective as structured weight-loss diets. MR simplifies the weight loss plan by replacing one or two meals a day with a product of defined nutrient and calorie content. MR leads to increased weight losses over twelve weeks compared to simply restricting the intake of favorite food, and weight losses have been shown to be maintain for up to 4 years with the inclusion of one MR per day. The present study was designed to recommend isocaloric weight management programs through the inclusion of either a protein or a carbohydrate supplement to a standard meal replacement powder to make either a standard or protein-enriched meal replacement.

These studies demonstrate that protein-enriched meals replacements as compared to standard meal replacements recommended for weight management do not have adverse effects on routine measures of liver function, renal function or bone density at one year.

Li Z, Treyzon L, Chen S, Yan E, Thames G, Carpenter CL. Protein-enriched meal replacements do not adversely affect liver, kidney or bone density: an outpatient randomized controlled trial. Nutr J 2011;9(1):72. http://www.nutritionj.com/content/pdf/1475-2891-9-72.pdf

BACKGROUND: There is concern that recommending protein-enriched meal replacements as part of a weight management program could lead to changes in biomarkers of liver or renal function and reductions in bone density. This study was designed as a placebo-controlled clinical trial utilizing two isocaloric meal plans utilizing either a high protein-enriched (HP) or a standard protein (SP) meal replacement in an outpatient weight loss program. Subjects/methods: 100 obese men and women over 30 years of age with a body mass index (BMI) between 27 to 40 kg/m2 were randomized to one of two isocaloric weight loss meal plans 1). HP group: providing 2.2 g protein/kg of lean body mass (LBM)/day or 2). SP group: providing 1.1 g protein/kg LBM/day. Meal replacement (MR) was used twice daily (one meal, one snack) for 3 months and then once a day for 9 months. Body weight, lipid profiles, liver function, renal function and bone density were measured at baseline and 12 months.

RESULTS: Seventy subjects completed the study. Both groups lost weight (HP -4.29 +/- 5.90 kg vs. SP -4.66 +/- 6.91 kg, p<0.01) and there was no difference in weight loss observed between the groups at one year. There was no significant change noted in liver function [AST (HP -2.07 +/- 10.32 U/L, p=0.28; SP 0.27+/- 6.67 U/L, p=0.820), ALT (HP -1.03 +/- 10.08 U/L, p=0.34; SP -2.6 +/- 12.51 U/L, p=0.24), bilirubin (HP 0.007+/-0.33, U/L, p=0.91; SP 0.07+/-0.24 U/L, p=0.120), alkaline phosphatase (HP 2.00+/- 9.07 U/L, p=0.240; SP -2.12+/- 11.01 U/L, p=0.280)], renal function [serum creatinine (HP 0.31 +/- 1.89 mg/dL, p=0.380; SP -0.05+/- 0.15 mg/dL, p=0.060), urea nitrogen (HP 1.33 +/- 4.68 mg/dL, p=0.130; SP -0.24+/- 3.03 mg/dL, p=0.650), 24 hour urine creatinine clearance (HP -0.02 +/- 0.16 mL/min, p=0.480; SP 1.18+/- 7.53 mL/min, p=0.400), and calcium excretion (HP -0.41 +/- 9.48 mg/24 hours, p=0.830; SP -0.007+/- 6.76 mg/24 hours, p=0.990)] or in bone mineral density by DEXA (HP 0.04 +/- 0.19 g/cm2, p=0.210; SP -0.03+/- 0.17 g/cm2, p=0.320) in either group over one year.

CONCLUSIONS: These studies demonstrate that protein-enriched meals replacements as compared to standard meal replacements recommended for weight management do not have adverse effects on routine measures of liver function, renal function or bone density at one year.

 

[Michael Scally MD]

According to a study in the British Medical Journal, "people who walked the most after five years not only had a lower body mass index," but were also "less likely to develop diabetes." Researchers examined "592 middle-aged adults" and reevaluated them "five years later." The investigators concluded, “a higher daily step count at five year follow-up than at baseline was associated with better insulin sensitivity. This effect seems to be largely mediated through lower adiposity.”


Dwyer T, Ponsonby AL, Ukoumunne OC, et al. Association of change in daily step count over five years with insulin sensitivity and adiposity: population based cohort study. BMJ 2011;342. Association of change in daily step count over five years with insulin sensitivity and adiposity: population based cohort study -- Dwyer et al. 342 -- bmj.com

Objectives To investigate the association between change in daily step count and both adiposity and insulin sensitivity and the extent to which the association between change in daily step count and insulin sensitivity may be mediated by adiposity.

Design Population based cohort study.

Setting Tasmania, Australia.

Participants 592 adults (men (n=267), mean age 51.4 (SD 12.2) years; women (n=325), mean age 50.3 (12.3) years) who participated in the Tasmanian component of the national AusDiab Study in 2000 and 2005.

Main outcome measures Body mass index, waist to hip ratio, and HOMA insulin sensitivity at follow-up in 2005.

Results Over the five year period, the daily step count decreased for 65% (n=382) of participants. Having a higher daily step count in 2005 than in 2000 was independently associated with lower body mass index (0.08 (95% confidence interval 0.04 to 0.12) lower per 1000 steps), lower waist to hip ratio (0.15 (0.07 to 0.23) lower), and greater insulin sensitivity (1.38 (0.14 to 2.63) HOMA units higher) in 2005. The mean increase in HOMA units fell to 0.34 (−0.79 to 1.47) after adjustment for body mass index in 2005.

Conclusions Among community dwelling, middle aged adults, a higher daily step count at five year follow-up than at baseline was associated with better insulin sensitivity. This effect seems to be largely mediated through lower adiposity.

 

[Michael Scally MD]

The 5-ARIs clearly have an effect on AR cascade. Whether this has some import to the adverse sexual effects described is unknown, but there appears to possibly be some link. The puzzle is for continued effects after 5-ARI discontinuation.


Hsieh JT, Chen SC, Yu HJ, Chang HC. Finasteride upregulates expression of androgen receptor in hyperplastic prostate and LNCaP cells: Implications for chemoprevention of prostate cancer. Prostate. 2011 Jan 12. Finasteride upregulates expression of androgen rec... [Prostate. 2011] - PubMed result

BACKGROUND: Although finasteride is recognized for its role as a chemopreventive agent for prostate cancer, higher grades of malignancy have been reported. It is questioned whether blocking of testosterone conversion to dihydrotestosterone (DHT) by finasteride in prostate tissue will change expression of androgen receptor (AR). Therefore, this study evaluated the effects of finasteride on AR expression in prostate tissue and in the LNCaP cell line.

METHODS: Between January and December 2006, we retrospectively selected and evaluated 47 cases of benign prostatic hyperplasia treated with variable duration of finasteride (5 mg QD) before transurethral resection of the prostate. AR expression in prostate tissue was semiquantified by immunostaining and compared with duration of finasteride treatment. An androgen-dependent prostate cancer cell line (LNCaP) was cultured in charcoal/dextran-treated FBS with DHT or testosterone, and treated with finasteride for 1-3 weeks. Samples of total RNA were collected to analyze expression of AR by real-time quantitative reverse transcription polymerase chain reaction.

RESULTS: Immunohistochemical study revealed significant upregulation of ARs by finasteride treatment for 30-180 days. In cell line study, quantitative real-time reverse transcription polymerase chain reaction revealed significant upregulation of ARs treated by finasteride.

CONCLUSIONS: In our study, finasteride influenced AR expression in benign prostate tissue and prostate cancer cell. Before we can use finasteride in chemoprevention with confidence, we still need to clarify the influence of finasteride in ARs and its regulation pathway.

 

[Michael Scally MD]

Violent thoughts and acts towards others area common occurrence in our society but rarely studied as an adverse drug event. Increased risk of suicidal behaviors—but not violence— associated with antidepressants has been examined through meta-analysis of clinical trials for approval by the U.S. Food and Drug Administration.

Despite limited clinical study, numerous drugs contain FDA-required warnings to doctors or patients about the possibility of aggressive or violent acts. Among the drugs with warnings about aggressive behaviors are varenicline, zolpidem, montelukast, and all antidepressant drugs. The mandatory patient Medication Guide for varenicline, the antidepressants and quetiapine warn patients to contact a healthcare provider immediately if they start “acting aggressive, being angry or violent.”

In this study, they summarize and evaluate the evidence about reported acts of violence associated with therapeutic drugs among all serious adverse drug events reported to the FDA from 2004 through the third quarter of 2009. Most of the drugs in the top ten most dangerous are antidepressants, but also included are an insomnia medication, an attention-deficit hyperactivity disorder (ADHD) drug, a malaria drug and an anti-smoking medication.

The top ten list is as follows:

1. Varenicline (Chantix) - An anti-smoking drug that is a shocking 18 times more likely to be associated with violence than other drugs.

2. Fluoxetine (Prozac) - A popular SSRI antidepressant drug that is 10.9 times more likely to be associated with violence than other drugs.

3. Paroxetine (Paxil) - An SSRI antidepressant drug that is 10.3 times more likely to be associated with violence than other drugs. It is also linked to severe withdrawal symptoms and birth defects.

4. Amphetamines - This general class of ADHD drug is 9.6 times more likely to be associated with violence than other drugs.

5. Mefoquine (Lariam) - A malaria drug that is 9.5 times more likely to be associated with violence than other drugs.

6. Atomoxetine (Strattera) - An ADHD drug that is 9 times more likely to be associated with violence than other drugs.

7. Triazolam (Halcion) - A benzodiazepine drug for insomnia that is 8.7 times more likely to be associated with violence than other drugs.

8. Fluvoxamine (Luvox) - A selective serotonin reuptake inhibitor (SSRI) drug that is 8.4 times more likely to be associated with violence than other drugs.

9. Venlafaxine (Effexor) - An antidepressant that treats anxiety disorders. The drug is 8.3 times more likely to be associated with violence than other drugs.

10. Desvenlafaxine (Pristiq) - An antidepressant that affects serotonin and noradrenaline. The drug is 7.9 times more likely to be associated with violence than other drugs.


Moore TJ, Glenmullen J, Furberg CD. Prescription Drugs Associated with Reports of Violence Towards Others. PLoS ONE 2010;5(12):e15337. PLoS ONE: Prescription Drugs Associated with Reports of Violence Towards Others

CONTEXT: Violence towards others is a seldom-studied adverse drug event and an atypical one because the risk of injury extends to others.

OBJECTIVE: To identify the primary suspects in adverse drug event reports describing thoughts or acts of violence towards others, and assess the strength of the association.

METHODOLOGY: From the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) data, we extracted all serious adverse event reports for drugs with 200 or more cases received from 2004 through September 2009. We identified any case report indicating homicide, homicidal ideation, physical assault, physical abuse or violence related symptoms.

MAIN OUTCOME MEASURES: Disproportionality in reporting was defined as a) 5 or more violence case reports, b) at least twice the number of reports expected given the volume of overall reports for that drug, c) a ?2 statistic indicating the violence cases were unlikely to have occurred by chance (p<0.01).

RESULTS: We identified 1527 cases of violence disproportionally reported for 31 drugs. Primary suspect drugs included varenicline (an aid to smoking cessation), 11 antidepressants, 6 sedative/hypnotics and 3 drugs for attention deficit hyperactivity disorder. The evidence of an association was weaker and mixed for antipsychotic drugs and absent for all but 1 anticonvulsant/mood stabilizer. Two or fewer violence cases were reported for 435/484 (84.7%) of all evaluable drugs suggesting that an association with this adverse event is unlikely for these drugs.

CONCLUSIONS: Acts of violence towards others are a genuine and serious adverse drug event associated with a relatively small group of drugs. Varenicline, which increases the availability of dopamine, and antidepressants with serotonergic effects were the most strongly and consistently implicated drugs. Prospective studies to evaluate systematically this side effect are needed to establish the incidence, confirm differences among drugs and identify additional common features.

 

[Michael Scally MD]

In 1999, a 24-year-old Swedish male was diagnosed with androgenic alopecia (AGA). He had normal stature (height, 182 cm; weight, 80 kg), had no history of any medical illness, and was not taking any medications. He reported having a normal sex drive and normal erectile capacity. He started treatment with finasteride (Propecia™), 1 mg daily, and within 2–5 days experienced soreness of the testicles, total lack of sex drive, and complete inability to achieve an erection. He had difficulty concentrating, and felt depressed. Expecting these initial side effects to be temporary, he continued treatment. Except for some improvement of the soreness in the testicles, he felt numb and there was no improvement in his sex drive or erectile function. After a little more than 1 month, he discontinued treatment and the side effects diminished to some degree, but sexual function never returned to normal. In the following months and years, the symptoms persisted with loss of libido and erectile dysfunction (ED). In 2003, the patient consulted a specialty clinic for sexual medicine in Boston, MA, USA, and went through extensive examinations. At this point, treatment with Viagra had been tried with only marginal success. Because of hopelessness and depression, two types of antidepressants (citalopram and bupropion) had been prescribed, which helped by “taking away the deepest lows,” but with no improvement in either libido or erectile capacity. In addition, there were undesirable side effects to these drugs and treatment was discontinued after several months. In Boston, the patient had a psychological evaluation and again underwent duplex Doppler ultrasonography.

Suffering from persistent symptoms of ED, loss of libido, and depression, the patient consulted a clinic in Copenhagen, Denmark, which specializes in testosterone treatment. The total testosterone (T) varied between 22.6 and 14.2 nmol/L (651 and 409 ng/dL) in the baseline state. The fluctuations were felt to be quite wide. No 5 adihydrotestosterone (5 a-DHT) measurements were available. The following baseline tests were all found to be normal: sex hormone binding globulin, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, T3, T4, prolactin, estradiol, DHEA-S, and androstenedione. He is currently under no treatment, but 11 years later, he still suffers from ED and loss of libido.


Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML. Adverse Side Effects of 5alpha-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients. J Sex Med. Adverse Side Effects of 5?-Reductase Inhibitors Th... [J Sex Med. 2010] - PubMed result

Introduction. 5alpha-reductase inhibitors (5alpha-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined.

Aim. The goal of this review is to discuss 5alpha-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects.

Methods. We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride.

Main Outcome Measures. Data reported in the literature were reviewed and discussed.

Results. Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship.

Conclusions. We suggest discussion with patients on the potential sexual side effects of 5alpha-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.


Author Information

Abdulmaged M. Traish PhD, Departments of Biochemistry and of Urology, Boston University School of Medicine, Boston, MA, USA

John Hassani MA, Departments of Biochemistry and of Urology, Boston University School of Medicine, Boston, MA, USA

Andre T. Guay MD, Center for Sexual Function/Endocrinology Lahey Clinic, Northshore, Peabody, MA, USA

Michael Zitzmann D, PhD, Centre for Reproductive Medicine and Andrology/Clinical Andrology Domagkstrasse 11 University Clinics Muenster, Germany

Michael L. Hansen MD, Department of OB/GYN, Stavanger University Hospital, Stavanger, Norway

 

[Michael Scally MD]

Mauvais-Jarvis F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends in Endocrinology & Metabolism 2011;22(1):24-33. Estrogen and androgen receptors: regulators of fue... [Trends Endocrinol Metab. 2011] - PubMed result

Because of increasing life expectancy, the contribution of age-related estrogen or androgen deficiency to obesity and type 2 diabetes will become a new therapeutic challenge. This review integrates current concepts on the mechanisms through which estrogen receptors (ERs) and androgen receptor (AR) regulate energy homeostasis in rodents and humans. In females, estrogen maintains energy homeostasis via ER? and ER?, by suppressing energy intake and lipogenesis, enhancing energy expenditure, and ameliorating insulin secretion and sensitivity. In males, testosterone is converted to estrogen and maintains fuel homeostasis via ERs and AR, which share related functions to suppress adipose tissue accumulation and improve insulin sensitivity. We suggest that ERs and AR could be potential targets in the prevention of age-related metabolic disorders.


Franck Mauvais-Jarvis - Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, and Comprehensive Center on Obesity, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. f-mauvais-jarvis@northwestern.edu

 

[Michael Scally MD]

Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the Primary Prevention of Stroke. A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. Guidelines for the Primary Prevention of Stroke. A... [Stroke. 2010] - PubMed result - Full Text: Guidelines for the Primary Prevention of Stroke. A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association -- Goldstein et al., 10.1161/STR.0b013e3181fcb238 -- Stroke

BACKGROUND AND PURPOSE: This guideline provides an overview of the evidence on established and emerging risk factors for stroke to provide evidence-based recommendations for the reduction of risk of a first stroke.

METHODS: Writing group members were nominated by the committee chair on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council Scientific Statement Oversight Committee and the AHA Manuscript Oversight Committee. The writing group used systematic literature reviews (covering the time since the last review was published in 2006 up to April 2009), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate recommendations using standard AHA criteria (Tables 1 and 2). All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. The guideline underwent extensive peer review by the Stroke Council leadership and the AHA scientific statements oversight committees before consideration and approval by the AHA Science Advisory and Coordinating Committee.

RESULTS: Schemes for assessing a person's risk of a first stroke were evaluated. Risk factors or risk markers for a first stroke were classified according to potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented or less well documented). Nonmodifiable risk factors include age, sex, low birth weight, race/ethnicity, and genetic predisposition. Well-documented and modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, atrial fibrillation and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, excessive alcohol consumption, drug abuse, use of oral contraceptives, sleep-disordered breathing, migraine, hyperhomocysteinemia, elevated lipoprotein(a), hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are reviewed.

CONCLUSIONS: Extensive evidence identifies a variety of specific factors that increase the risk of a first stroke and that provide strategies for reducing that risk.


Roger VL, Go AS, Lloyd-Jones DM, et al. Heart Disease and Stroke Statistics--2011 Update: A Report From the American Heart Association. Circulation. Heart Disease and Stroke Statistics--2011 Update: A Report From the American Heart Association -- Roger et al., 10.1161/CIR.0b013e3182009701 -- Circulation

Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on disease morbidity and mortality and the risks, quality of care, medical procedures and operations, and costs associated with the management of these diseases in a single document.

Indeed, since 1999, the Statistical Update has been cited more than 8700 times in the literature (including citations of all annual versions). In 2009 alone, the various Statistical Updates were cited ~1600 times (data from ISI Web of Science). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas. For this year’s edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year and added a new chapter detailing how family history and genetics play a role in cardiovascular disease (CVD) risk. Also, the 2011 Statistical Update is a major source for monitoring both cardiovascular health and disease in the population, with a focus on progress toward achievement of the AHA’s 2020 Impact Goals.

 

[Michael Scally MD]

High-dose sex steroid treatment to reduce final height of tall boys has been widely used. Possibly due to greater social acceptance of tall stature, fewer adolescent boys are treated these days. The treatment of tall stature is based on the understanding that exposure to gonadal steroids leads to epiphyseal fusion of the long bones during pubertal development. Commonly used treatment is an im-injected preparation of testosterone ester mixtures (Sustanon 250; Schering-Plough, Houten, The Netherlands) in a dose of 250 mg/wk for, on average, a period of 1.5 yr.

High doses of androgens are known to greatly reduce sperm production, which is reversible in adult men, although it sometimes may take years until full recovery. However, because in the maturing gonads the initiation of spermatogenesis is stimulated by hormones of the hypothalamic-pituitary-gonadal axis, treatment given during puberty may have lasting effects on pituitary-gonadal functioning. Therefore, several studies have looked at possible side effects of high-dose androgen treatment for tall stature.

Short-term side effects are well documented and include: weight gain, acne, gynecomastia, muscle ache, and edema. A few studies have reported on long-term fertility and reproductive function after a follow-up of up to 10 yr. One study found marginally higher serum FSH levels and lower serum LH levels in androgen-treated boys compared with untreated tall boys at an average follow-up of 10 yr. None have found significant effects on sperm quality or fertility. The aim of this single center retrospective cohort study was to evaluate fertility and testicular function in a cohort of tall Dutch men who did or did not receive high-dose androgen treatment in adolescence.

At a mean follow-up of 21 yr after high-dose androgen treatment, we conclude that fatherhood and semen quality in tall treated men are not affected. Serum testosterone levels, however, are reduced in androgen-treated men.


Hendriks AEJ, Boellaard WPA, van Casteren NJ, et al. Fatherhood in Tall Men Treated with High-Dose Sex Steroids during Adolescence. J Clin Endocrinol Metab 2010;95(12):5233-40. http://jcem.endojournals.org/cgi/content/abstract/95/12/5233 (Fatherhood in Tall Men Treated with High-Dose Sex Steroids during Adolescence -- Hendriks et al. 95 (12): 5233 -- Journal of Clinical Endocrinology &amp; Metabolism)

Background/Objective: Sex steroid treatment to reduce final height of tall boys has been available since the 1950s. In women, it has been shown to interfere with fertility. In men, no such data are available. We therefore evaluated fertility and gonadal function in tall men who did or did not receive high-dose androgen treatment in adolescence.

Methods: We conducted a retrospective cohort study of 116 tall men, of whom 60 had been treated. Reproductive and gonadal function was assessed by standardized interview, semen analysis, endocrine parameters, ultrasound imaging, and fatherhood. Mean age at treatment commencement was 14.2 yr, and mean follow-up was 21.2 yr.

Results: Sixty-six men (36 treated and 30 untreated) had attempted to achieve fatherhood. The probability of conceiving their first pregnancy within 1 yr was similar in treated and untreated men (26 vs. 24; Breslow P = 0.8). Eleven treated and 13 untreated men presented with a left-sided varicocele (P = 0.5). Testicular volume, sperm quality, and serum LH, FSH, and inhibin B levels were comparable between treated and untreated men. However, treated men had significantly reduced serum T levels, adjusted for known confounders [mean (sD) 13.3 (1.8) vs. 15.2 (1.9) nmol/liter; P = 0.005). In addition, testicular volume and serum inhibin B and FSH levels in treated men were significantly correlated with age at treatment commencement.

Conclusion: At a mean follow-up of 21 yr after high-dose androgen treatment, we conclude that fatherhood and semen quality in tall treated men are not affected. Serum testosterone levels, however, are reduced in androgen-treated men. Future research is required to determine whether declining testosterone levels may become clinically relevant for these men as they age.


A. E. J. Hendriks, M.D., Department of Pediatrics, Division of Endocrinology, Erasmus Medical Center-Sophia, Room Sp3435, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: a.e.j.hendriks@erasmusmc.nl.

 

[Michael Scally MD]

Brand JS, van der Tweel I, Grobbee DE, Emmelot-Vonk MH, van der Schouw YT. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. International Journal of Epidemiology. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies — Int J Epidemiol

Background Accumulating evidence suggests a sex-dependent role of circulating testosterone in the metabolic syndrome (MetS).

Methods We conducted a meta-analysis of observational studies (PubMed and EMBASE—1 May 2010) relating MetS to determinants of testosterone status [total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG)].

Results A total of 52 studies were identified, comprising 22?043 men and 7839 women and presenting relative risk (RR) estimates or hormone levels for subjects with and without MetS. Endogenous TT and FT levels were lower in men with MetS [TT mean difference?=??2.64?nmol/l, 95% confidence interval (CI) ?2.95 to ?2.32; FT standardized mean difference?=??0.26?pmol/l, 95% CI ?0.39 to ?0.13] and higher in women with MetS (TT mean difference?=?0.14?nmol/l, 95% CI 0.07–0.20; FT standardized mean difference?=?0.52?pmol/l, 95% CI 0.33–0.71) compared with those without. Similarly, men with higher TT levels had a lower MetS risk (RR estimate?=?0.38, 95% CI 0.28–0.50) whereas higher TT levels increased the risk of MetS in women (RR estimate?=?1.68, 95% CI 1.15–2.45). In both sexes, higher SHBG levels were associated with a reduced risk (men: RR estimate?=?0.29, 95% CI 0.21–0.41; women: RR estimate?=?0.30, 95% CI 0.21–0.42).

Conclusion This meta-analysis supports the presence of a sex-dependent association between testosterone and MetS: TT and FT levels are lower in men with MetS, whereas they are higher in women with MetS. There are no indications for a sex-specific association between SHBG and MetS. In both men and women, MetS is associated with lower SHBG levels.


Rees DA, Dayan CM. Commentary: Testosterone and the metabolic syndrome: cause or consequence? Int J Epidemiol. Commentary: Testosterone and the metabolic syndrome: cause or consequence? — Int J Epidemiol

The Metabolic Syndrome (MetS), which affects approximately 15–25% of the adult population, comprises a cluster of cardiovascular risk factors that include central obesity, hypertension, hypertriglyceridaemia, glucose intolerance/insulin resistance and reduced high-density lipoprotein cholesterol levels. The presence of the syndrome conveys a significantly increased risk of type 2 diabetes (T2DM) and cardiovascular disease, hence identifying interventions that reduce the prevalence of the syndrome must be viewed as a major public health priority. In this issue of the journal, Brand et al.1 report their findings from a systematic review and meta-analysis of observational studies, which examined the association between testosterone (both total and free), its major carrier protein sex hormone binding globulin (SHBG) and the MetS. Their findings confirm a gender-dependent association between testosterone and the MetS, in which total and free testosterone levels are lower in men with the MetS but higher in women with the MetS, compared with those without. How can these relationships be explained and what is the significance of their observations for clinical practice?

Clinicians treating men with the MetS and/or T2DM will recognize low testosterone readings in their patients as a common finding. A previous meta-analysis of 2900 men, 850 of whom had T2DM, showed that total testosterone was lowered by a mean of ?2.66?nmol/l in men with T2DM compared with their non-diabetic counterparts, an association that was partly attenuated but not eliminated when adjusted for age, body mass index (BMI) and waist-hip ratio (WHR).2 These findings in the diabetic population are similar to Brand et al.'s1 observations, where a similar pooled estimate for the difference in total testosterone between men with and without the MetS was noted. Since this relationship remained significant after adjustment for age and BMI, does this discount body fat as a mediator?

Adiposity may affect the hypothalamic-pituitary-gonadal axis by several mechanisms including luteinising hormone suppression secondary to increased production of both proinflammatory adipocytokines and oestrogen (generated by enhanced aromatization of testosterone), and hypothalamic leptin resistance.3 Regional fat depots may contribute differently to this relationship since aromatase activity is greater in visceral than subcutaneous fat. Importantly, Brand et al. were unable to adjust for regional adiposity since the studies which informed their analyses largely confined their assessments of adiposity to the relatively crude measures of BMI and WHR, hence residual confounding cannot be excluded. Indeed, a study of 221 non-diabetic men, which was able to adjust for regional adiposity by computed tomography (CT) imaging, showed that the inverse relationship of insulin resistance, a key component of the MetS, with testosterone was no longer significant when visceral fat was adjusted for.4 Although this suggests that visceral fat may be an important mediator of the association between low testosterone and the MetS, other studies have shown that regional differences in adiposity cannot provide the sole explanation since low testosterone levels are more strongly predictive of the MetS in lean than obese men5 and ethnic differences in total testosterone in healthy young men are partly explained by differences in insulin resistance but not by adiposity.6 The potential importance of insulin resistance as a key mediator for Brand and colleagues’ observations is underscored by their findings of a weaker association between total testosterone and the MetS when the NCEP ATP III criteria were used, which places less emphasis on glucose intolerance compared with other definitions of the MetS. Insulin resistance, which results in compensatory hyperinsulinaemia in subjects with the MetS, might also account for their findings of a strong inverse association between the MetS and SHBG levels in both sexes, since portal insulin levels are a major negative regulator of hepatic SHBG production.7 However, there is increasing evidence of a role for SHBG per se in the development of the MetS and T2DM, as illustrated by studies which identified germline variants of the SHBG gene that were predictive not only of SHBG levels but also for the development of T2DM.8,9 These results provide strong evidence for a causal role for low SHBG levels in the development of insulin resistance since interpretation of genetic associations is unaffected by confounding or reverse causation. Previous studies in men have shown that the association between free testosterone and the MetS/T2DM is less consistent than that for total testosterone, a finding which might point to SHBG as the key mediator in this relationship since low SHBG levels also result in a lowered total testosterone. Thus, the demonstration of a significant inverse association of free testosterone with the MetS in the Brand study is important and suggests that the relationship of testosterone with insulin resistance is not simply a result of its relationship with SHBG.

Brand and colleagues also confirm a positive association of total and free testosterone with the MetS in women, although the number of studies that informed their analyses were comparatively less than in men and all used a cross-sectional design. Hence, the conclusions that can be drawn from this section of the analysis must necessarily be guarded but it is interesting to note that interventions, such as flutamide and metformin, which have been shown to lower testosterone in women with polycystic ovary syndrome may also improve several components of the MetS,10,11 although it is unclear whether or not these benefits are mediated through improved insulin sensitivity.

Whereas the findings of this meta-analysis provide convincing evidence of a gender-specific association of testosterone with the MetS, the results are driven largely by cross-sectional studies that neither prove causation nor indeed demonstrate the direction of effect. In this context, it is intriguing to note that the few prospective studies undertaken in men to date have shown not only that low testosterone predicts the subsequent development of the MetS and T2DM but also that the converse may be true, namely that the MetS predicts the development of low testosterone.12 These studies point to a bidirectional relationship between testosterone and the MetS, although prospective epidemiological studies are themselves limited by the problem of reverse causation. We therefore share Brand and colleagues’ views that future studies in this area should embrace alternative approaches such as Mendelian randomization and interventional trials of testosterone lowering (in women) or replacement (in men), which must include measures of insulin resistance and regional adiposity, in order to establish whether testosterone has a causal role in the MetS.

References at link.

 

[Structure]

In 1999, a 24-year-old Swedish male was diagnosed with androgenic alopecia (AGA). He had normal stature (height, 182 cm; weight, 80 kg), had no history of any medical illness, and was not taking any medications. He reported having a normal sex drive and normal erectile capacity. He started treatment with finasteride (Propecia™), 1 mg daily, and within 2–5 days experienced soreness of the testicles, total lack of sex drive, and complete inability to achieve an erection. He had difficulty concentrating, and felt depressed. Expecting these initial side effects to be temporary, he continued treatment. Except for some improvement of the soreness in the testicles, he felt numb and there was no improvement in his sex drive or erectile function. After a little more than 1 month, he discontinued treatment and the side effects diminished to some degree, but sexual function never returned to normal. In the following months and years, the symptoms persisted with loss of libido and erectile dysfunction (ED). In 2003, the patient consulted a specialty clinic for sexual medicine in Boston, MA, USA, and went through extensive examinations. At this point, treatment with Viagra had been tried with only marginal success. Because of hopelessness and depression, two types of antidepressants (citalopram and bupropion) had been prescribed, which helped by “taking away the deepest lows,” but with no improvement in either libido or erectile capacity. In addition, there were undesirable side effects to these drugs and treatment was discontinued after several months. In Boston, the patient had a psychological evaluation and again underwent duplex Doppler ultrasonography.

Suffering from persistent symptoms of ED, loss of libido, and depression, the patient consulted a clinic in Copenhagen, Denmark, which specializes in testosterone treatment. The total testosterone (T) varied between 22.6 and 14.2 nmol/L (651 and 409 ng/dL) in the baseline state. The fluctuations were felt to be quite wide. No 5 adihydrotestosterone (5 a-DHT) measurements were available. The following baseline tests were all found to be normal: sex hormone binding globulin, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, T3, T4, prolactin, estradiol, DHEA-S, and androstenedione. He is currently under no treatment, but 11 years later, he still suffers from ED and loss of libido.


Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML. Adverse Side Effects of 5alpha-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients. J Sex Med. Adverse Side Effects of 5?-Reductase Inhibitors Th... [J Sex Med. 2010] - PubMed result

Introduction. 5alpha-reductase inhibitors (5alpha-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined.

Aim. The goal of this review is to discuss 5alpha-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects.

Methods. We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride.

Main Outcome Measures. Data reported in the literature were reviewed and discussed.

Results. Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship.

Conclusions. We suggest discussion with patients on the potential sexual side effects of 5alpha-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.


Author Information

Abdulmaged M. Traish PhD, Departments of Biochemistry and of Urology, Boston University School of Medicine, Boston, MA, USA

John Hassani MA, Departments of Biochemistry and of Urology, Boston University School of Medicine, Boston, MA, USA

Andre T. Guay MD, Center for Sexual Function/Endocrinology Lahey Clinic, Northshore, Peabody, MA, USA

Michael Zitzmann D, PhD, Centre for Reproductive Medicine and Andrology/Clinical Andrology Domagkstrasse 11 University Clinics Muenster, Germany

Michael L. Hansen MD, Department of OB/GYN, Stavanger University Hospital, Stavanger, Norway

Where did you find the case study on the 24-year old Swedish male? I can't find any references to it on the Internet, but I'd like to read more about it.

 

[Michael Scally MD]

The current issue of Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry, is devoted to myostatin. They have have assembled a group of thought leaders to review and assess the progress that has been made to date in this field. For anyone with an interest in myostatin, this is an excellent read. IMO, this has far greater potential for future clinical use than do SARMs. Where the full-text article is available, I have provided a link. For others, email me. http://www.bentham.org/cmciema/CurrentIssue.htm (BSP :: Immunology, Endocrine &amp; Metabolic Agents in Medicinal Chemistry Home Page)

It has now been 13 years since the original report in 1997 of the discovery of myostatin and its function as a negative regulator of muscle mass. Since that initial report, an enormous amount of effort in both the academic and the biotechnology/pharmaceutical research communities has been directed at understanding the biology of myostatin and developing strategies for exploiting its biological activity for clinical applications. These insights have fueled the development of therapeutic agents targeting this signaling pathway, and at least four companies have entered clinical trials with myostatin inhibitors to combat muscle loss.

The myostatin (MSTN) gene encodes a member of the transforming growth factor ? (TGF?) superfamily of secreted growth factors highly expressed in skeletal muscle. Mice, double muscled cattle, sheep, dogs, and one child with MSTN loss of function genetic mutations all have dramatically increased skeletal muscle mass demonstrating that the function of the MSTN gene is to negatively regulate skeletal muscle growth. This increased muscularity is due to hyperplasia, an increase in the absolute number of skeletal muscle fibers, and hypertrophy, an increase in the cross-sectional area of individual skeletal muscle fibers.


McPherron AC. Metabolic Functions of Myostatin and Gdf11. Immunol Endocr Metab Agents Med Chem 2010;10(4):217-31. METABOLIC FUNCTIONS OF MYOSTATIN AND GDF11

Myostatin is a member of the transforming growth factor beta superfamily of secreted growth factors that negatively regulates skeletal muscle size. Mice null for the myostatin gene have a dramatically increased mass of individual muscles, reduced adiposity, increased insulin sensitivity, and resistance to obesity. Myostatin inhibition in adult mice also increases muscle mass which raises the possibility that anti-myostatin therapy could be a useful approach for treating diseases such as obesity or diabetes in addition to muscle wasting diseases. In this review I will describe the present state of our understanding of the role of myostatin and the closely related growth factor growth/differentiation factor 11 on metabolism.


Wilkinson HA. Role of Myostatin Signaling in Aging: Applications for Age Related Sarcopenia. Immunol Endocr Metab Agents Med Chem 2010;10(4):211-16. http://www.bentham.org/cmciema/openaccessarticles/10-4/0005P[1].pdf

Myostatin is a member of the TGF beta family which is known to promote muscle wasting. Reduction of function mutations in this signaling molecule results in increased muscle mass in many different species examined including mice and humans. Age-related sarcopenia results in loss of strength and is a major contributing factor to falls and loss of independence in the elderly. Studies in rodents have demonstrated a decrease in myostatin expression in skeletal muscle whereas in humans there appears to be an increase in myostatin expression with age. Myostatin knockout mice have been reported to be resistant to the development of age-related sarcopenia and in humans, myostatin polymorphisms have been correlated with changes in muscle mass in the elderly. Treatment with an inhibitory antibody to myostatin increases muscle mass and, in combination with exercise, improves physical performance and metabolic parameters in aged mice and inhibition of myostatin pathway signaling with a dominant negative protein in aged mice speeds muscle regeneration after injury. Studies in old mice and rats suggest inhibition or loss of myostatin improves key features of skeletal muscle organization which are compromised in age-related sarcopenia and understanding the role of myostatin in aging skeletal muscle may reveal potential novel therapies for this unmet medical need.


Lee S-J. Extracellular Regulation of Myostatin: A Molecular Rheostat for Muscle Mass. Immunol Endocr Metab Agents Med Chem 2010;10(4):183-94. http://www.bentham.org/cmciema/openaccessarticles/10-4/0002P.pdf

Myostatin (MSTN) is a transforming growth factor-ß family member that plays a critical role in regulating skeletal muscle mass. Genetic studies in multiple species have demonstrated that mutations in theMstn gene lead to dramatic and widespread increases in muscle mass as a result of a combination of increased fiber numbers and increased fiber sizes. MSTN inhibitors have also been shown to cause significant increases in muscle growth when administered to adult mice. As a result, there has been an extensive effort to understand the mechanisms underlying MSTN regulation and activity with the goal of developing the most effective strategies for targeting this signaling pathway for clinical applications. Here, I review the current state of knowledge regarding the regulation of MSTN extracellularly by binding proteins and discuss the implications of these findings both with respect to the fundamental physiological role that MSTN plays in regulating tissue homeostasis and with respect to the development of therapeutic agents to combat muscle loss.


Tu P, Bhasin S, Guo W. Myostatin Inhibition and Cardiometabolic Disorders. Endocr Metab Agents Med Chem 2010;10:232-39.

Age-associated loss of skeletal muscle mass and strength, termed sarcopenia, is a major public health concern. Individuals with sarcopenia and frailty have decreased physical function and are at increased risk of cardiovascular and metabolic disorders. Despite the remarkable gains in the human health span, cardiometabolic disorders remain the leading cause of mortality worldwide. Here, we discuss the potential therapeutic implications of promyogenic function promoting anabolic agents, particularly myostatin antagonists, in the prevention of a variety of age-related metabolic disorders.


Georges M. When Less Means More: Impact of Myostatin in Animal Breeding. Endocr Metab Agents Med Chem 2010;10:240-48.

Increasing muscle mass is one of the primary breeding objectives in domestic animals as it translates in enhanced carcass yield in livestock or improved athletic performances in companion animals. Naturally occurring loss-of-function mutations in the MSTN gene have been shown to underlie the “double-muscling” phenotype in cattle, the “increased muscle mass” phenotype in sheep and the “bully” phenotype in sprinter dogs. Hypomorphic MSTN alleles associated with weaker but sometimes more advantageous effects on muscle mass have been identified in cattle and sheep. MSTN is a prime target for transgenic approaches aimed at enhancing meat production in livestock. Strategies that are being explored include the generation of MSTN “knock-out” animals and the expression in skeletal muscle of MSTN trans-inhibitors. More elaborate transgenic approaches targeting post-natal or sex-specific inhibition of MSTN are also being pursued. Finally, MSTN is an obvious target for pharmacological inhibition as well as immunomodulation with the aim to increase muscle mass in animals.


Wagner KR. Clinical Applications of Myostatin Inhibitors for Neuromuscular Diseases. Immunol Endocr Metab Agents Med Chem 2010;10:204-10.

Hundreds of thousands of individuals suffer disability from skeletal muscle weakness associated with neuromuscular disease. Inhibition of the TGF-? family member, myostatin, may mitigate symptoms in these disorders regardless of the primary disease pathophysiology. There is substantial preclinical data that primary muscle disorders may benefit from myostatin inhibition. In particular, several mouse models of various muscular dystrophies have demonstrated amelioration of pathology and weakness with loss or inhibition of myostatin. There is also preclinical data that myostatin inhibition may increase muscle mass and strength in some denervating diseases. In addition to increasing the quantity of muscle, myostatin inhibition improves the quality of muscle by stimulating muscle regeneration and decreases muscle fibrosis in animal models. Clinical experience with myostatin inhibitors is still limited and the potential negative consequences of long term inhibition are unknown but may include replicative senescence of muscle progenitor cells, tendon shortening and off-target side effects. Clinical trials in disease populations as well as long term treatment studies in large animal models are now required to determine the appropriate clinical use of this novel therapeutic.

 

[Michael Scally MD]

Vitamin D deficiency is endemic in the general population; however, there is much to be learned about the vitamin D status of athletes.


Halliday T, Peterson N, Thomas J, Kleppinger K, Hollis B, Larson-Meyer D. Vitamin D Status Relative to Diet, Lifestyle, Injury and Illness in College Athletes. Med Sci Sports Exerc. Vitamin D Status Relative to Diet, Lifestyle, Inju... [Med Sci Sports Exerc. 2010] - PubMed result

PURPOSE:: To assess the prevalence of vitamin D insufficiency in collegiate athletes and determine whether 25(OH)D concentrations are related to vitamin D intake, sun exposure, body composition, and risk for illness or athletic injury.

METHODS:: 25(OH) vitamin D concentrations were measured in 41 (18 male/23 female) athletes (12 indoor/29 outdoor) throughout the academic year. Dietary intake and lifestyle habits were assessed via questionnaire, bone density was measured by DEXA and injury and illness were documented as part of routine care.

RESULTS:: 25(OH)D concentrations changed across time (P=0.001) and averaged 49.0+/-16.6, 30.5+/-9.4 and 41.9+/-14.6 ng/mL in the fall, winter and spring, respectively, and were higher in outdoor versus indoor athletes in the fall (P <0.05). Using 40 ng/mL as the cutoff for optimal status, 75.6 %, 15.2% and 36.0% of athletes had optimal status in the fall, winter and spring, respectively. 25(OH)D concentrations were significantly (P <0.05) correlated with multivitamin intake in the winter (r=0.39) and tanning bed use in the spring (r=0.48), however, status was otherwise not related to intake, lifestyle factors or body composition. 25(OH)D concentrations in the spring (r=-0.40; P=0.048) was correlated with frequency of illness.

CONCLUSION:: Our results suggest that collegiate athletes can maintain sufficient status during the fall and spring but would benefit from supplementation during the winter to prevent seasonal decreases in 25(OH)D concentrations. Results further suggest that insufficient vitamin D status may increase risk for frequent illness. Future research is needed to identify whether vitamin D status influences injury risk during athletic training/competition.

 

[Michael Scally MD]

Re: Post Orgasmic Illness Syndrome (POIS)

Waldinger MD, Meinardi MMHM, Zwinderman AH, Schweitzer DH. Postorgasmic Illness Syndrome (POIS) in 45 Dutch Caucasian Males: Clinical Characteristics and Evidence for an Immunogenic Pathogenesis (Part 1). The Journal of Sexual Medicine:no-no. http://onlinelibrary.wiley.com/doi/10.1111/j.1743-6109.2010.02166.x/abstract

Introduction. Postorgasmic illness syndrome (POIS) is a combination of local allergic symptoms and transient flu-like illness. In this study, the investigators propose five preliminary criteria to establish the diagnosis.

Aim. To describe the clinical details in 45 males being suspected of having POIS and to test an immunogenic hypothesis as the underlying mechanism of their presentations.

Methods. Forty-five males were studied according to standardized protocol, including neuropsychiatric and medical sexological evaluations; their complaints were categorized using their own words, and their self-perceived intravaginal ejaculation latency time (IELT). Skin-prick testing with autologous diluted Clinical features?semen in 33 men were also performed. Main Outcome Measures. of POIS including self-perceived IELTs and the results of skin-prick testing with autologous diluted seminal fluid.

Results. Of the 45 included men, 33 subjects consented with skin-prick testing. Of them, 29 (88%) men had a positive skin-prick test with their own (autologous) semen, and four had a negative test. In 87% of men, POIS symptoms started within 30 minutes after ejaculation. Complaints of POIS were categorized in seven clusters of symptoms, e.g., general, flu-like, head, eyes, nose, throat, and muscles. Local allergic reactions of eyes and nose were reported in 44% and 33% of subjects, a flu-like syndrome in 78% of subjects, exhaustion and concentration difficulties in 80% and 87% of subjects. Of all subjects, 58% had an atopic constitution. Lifelong premature ejaculation, defined as self-perceived IELT <1 minute, was reported in 25 (56%) of subjects.

Conclusions. The combination of allergic and systemic flu-like reactions post-ejaculation together with a positive skin-prick test in the majority of males underscores the hypothesis of an “immunogenic” etiology of POIS, e.g., that POIS is caused by Type-1 and Type-IV allergy to the males' own semen, as soon it is triggered by ejaculation.


Waldinger MD, Meinardi MMHM, Schweitzer DH. Hyposensitization Therapy with Autologous Semen in Two Dutch Caucasian Males: Beneficial Effects in Postorgasmic Illness Syndrome (POIS; Part 2). The Journal of Sexual Medicine:no-no. Hyposensitization Therapy with Autologous Semen in Two Dutch Caucasian Males: Beneficial Effects in Postorgasmic Illness Syndrome (POIS; Part 2) - Waldinger - 2011 - The Journal of Sexual Medicine - Wiley Online Library

Introduction. Postorgasmic illness syndrome (POIS) is a post-ejaculatory complex of local and/or systemic symptoms that nearly always occurs within seconds, minutes, or hours post-masturbation, coitus, or spontaneous ejaculation. Recent data suggest an autoimmunogenic/allergic underlying mechanism.

Aim. To treat males with POIS by hyposensitization with their own semen (autologous semen).

Methods. Two males suffering from POIS, of which one male with coincidental lifelong premature ejaculation (PE) were investigated. Based on their local and systemic symptoms including a positive dermatologic reaction after skin-prick testing with autologous semen, auto-allergy to semen was likely an underlying mechanism. A hyposensitization program was initiated, including multiple subcutaneous (SC) injections with autologous semen, initially at 2 weeks intervals in the first year and gradually at 4 weeks intervals in the second and third year. From initial semen dilutions of 1 on 40,000 and 1 on 20,000, the titers were gradually increased to 1 on 20 and 1 to 280, respectively.

Main Evaluation with a dedicated questionnaire about severity of?Outcome Measures. POIS symptoms and specialized interviews on self-perceived intravaginal ejaculation latency times (IELT) before and during the desensitization program.

Results. POIS was confirmed in both subjects, PE was confirmed in one male, and skin-prick tests with autologous semen in both subjects were positive. During the program, gradual reduction of complaints resulted in 60% and 90% amelioration of POIS complaints at 31 and 15 months, respectively, which coincided in one male with a delay of the IELT from 20 seconds at baseline to 10 minutes after 3 years of treatment. The cause of this association with IELT is unknown and remains to be elucidated.

Conclusions. Two males with POIS were successfully treated by hyposensitization with autologous semen, which supports an immunogenic/allergic etiology and underscores the clinical implication for immunological sexual medicine.

 

[Michael Scally MD]

Suicide is a disproportionate cause of mortality for physicians relative to both the general population and other professionals. Although suicide is strongly linked to depression, the lifetime risk of depression among physicians is similar to that of the general US population. This observation suggests that other factors may contribute to the increased risk of suicide among physicians. Access to lethal medications and knowledge of how to use them has been suggested as 1 factor; however, the influence of professional characteristics and forms of distress other than depression (eg, burnout) are largely unexplored.

The prevalence of suicidal ideation (SI) in the previous 12 months for the general US population is approximately 3.3%. The 2003 National Comorbidity Survey found that approximately one-third of individuals with SI make a plan, 72% of those with a plan make an attempt, and 26% proceed directly from SI to an unplanned attempt. In aggregate, these statistics suggest that as many as 50% of individuals with SI may eventually make a suicide attempt, with the majority of attempts occurring within 1 year of onset of SI. Recent data suggest that the increased risk for suicide among physicians may begin as early as medical school.

In the study reported here, commissioned by the American College of Surgeons (ACS) Committee on Physician Competency and Health, they evaluated the frequency of SI and the use of mental health resources among surgeons who were members of the ACS and measured the relationship between SI and surgeon burnout, quality of life (QOL), and symptoms of depression as assessed by standardized metrics.


Shanafelt TD, Balch CM, Dyrbye L, et al. Special Report: Suicidal Ideation Among American Surgeons. Arch Surg;146(1):54-62. Arch Surg -- Abstract: Special Report: Suicidal Ideation Among American Surgeons, January 2011, Shanafelt et al. 146 (1): 54

Background Suicide is a disproportionate cause of death for US physicians. The prevalence of suicidal ideation (SI) among surgeons and their use of mental health resources are unknown.

Study Design Members of the American College of Surgeons were sent an anonymous cross-sectional survey in June 2008. The survey included questions regarding SI and use of mental health resources, a validated depression screening tool, and standardized assessments of burnout and quality of life.

Results Of 7905 participating surgeons (response rate, 31.7%), 501 (6.3%) reported SI during the previous 12 months. Among individuals 45 years and older, SI was 1.5 to 3.0 times more common among surgeons than the general population (P < .02). Only 130 surgeons (26.0%) with recent SI had sought psychiatric or psychologic help, while 301 (60.1%) were reluctant to seek help due to concern that it could affect their medical license. Recent SI had a large, statistically significant adverse relationship with all 3 domains of burnout (emotional exhaustion, depersonalization, and low personal accomplishment) and symptoms of depression. Burnout (odds ratio, 1.910; P < .001) and depression (odds ratio, 7.012; P < .001) were independently associated with SI after controlling for personal and professional characteristics. Other personal and professional characteristics also related to the prevalence of SI.

Conclusions Although 1 of 16 surgeons reported SI in the previous year, few sought psychiatric or psychologic help. Recent SI among surgeons was strongly related to symptoms of depression and a surgeon's degree of burnout. Studies are needed to determine how to reduce SI among surgeons and how to eliminate barriers to their use of mental health resources.

 

[Michael Scally MD]

Lubricants designed for use during sexual activity are commonly sold through drug stores, large retail chains, the internet, adult bookstores, women-oriented sex boutiques, and in home sex toy parties in the United States. In the past decade, an expanded range of lubricants has been marketed to adults in the United States, resulting in more consumer choices and a greater visibility of lubricant products in mainstream retail spaces and advertising. In spite of their widespread availability, little is known about how and why women and men use lubricant during solo or partnered sexual activities or whether lubricant use has become less stigmatized with greater visibility and marketing of these products.


Herbenick D, Reece M, Hensel D, Sanders S, Jozkowski K, Fortenberry JD. Association of Lubricant Use with Women's Sexual Pleasure, Sexual Satisfaction, and Genital Symptoms: A Prospective Daily Diary Study. The Journal of Sexual Medicine 2011;8(1):202-12. Association of Lubricant Use with Women's Sexual P... [J Sex Med. 2011] - PubMed result

Introduction.? Although lubricant use is commonly recommended to women for solo and partnered sexual activities, little is known about women's use of lubricant or their relationship to sexual pleasure and satisfaction.

Aim.? The aim of this study was to assess: (i) how adult women used lubricant during partnered and solo sexual activities; (ii) relations between women's reports of sexual pleasure and satisfaction and their use of a lubricant during a particular sexual event; and (iii) to what extent lubricant use was associated with subsequent genital symptoms.

Methods.? A total of 2,453 women completed a 5-week internet-based, double-blind prospective daily diary study in which they were assigned to use one of six water- or silicone-based lubricants. Main Outcome Measures.? Baseline data included demographics, contraceptive use, and sexual behavior during the 4 weeks prior to study enrollment. Daily diary data included reports of penile–vaginal sex, penile–anal sex, solo sex, lubricant use, lubricant application, ratings of sexual pleasure and satisfaction, and genital symptoms.

Results.? Water-based lubricants were associated with fewer genital symptoms compared with silicone-based lubricants. In addition, the use of a water-based or silicone-based lubricant was associated with higher ratings of sexual pleasure and satisfaction for solo sex and penile–vaginal sex. Water-based lubricant use was associated with higher ratings of sexual pleasure and satisfaction for penile–anal sex as compared with no lubricant use.

Conclusion.? The water- and silicone-based lubricants used in this study were associated with significantly higher reports of sexual pleasure and satisfaction and rarely associated with genital symptoms.

 

[Michael Scally MD]

Over the past two decades, several studies have measured women’s and men’s feelings and beliefs about their own genitals or genitals more globally. An understanding of what have been called attitudes toward genitals, genital perceptions, and genital self-image is increasingly important given the range of ways that people interact with or make choices about their own or others’ genitals.

A reliable and valid measure of female genital self-image may be useful to researchers as well as clinicians, who may see women in relation to concerns about genital odor, appearance, or function. Previous research has demonstrated that female genital self-image is related to women’s engagement in sexual behaviors such as vibrator use and receptive cunnilingus, in addition to sexual function as reflected by scores on the Female Sexual Function Index (FSFI). Although several researchers have proposed scales to measure female genital self-image or perceptions, no one measure is widely in use. This may reflect the limited, and relatively recent, attention to the study of women’s genitals or female genital self-image. Alternatively, it may reflect concerns about the potential problems related to the internal validity of previously presented scales. Given the varied ways that researchers have measured the construct of female genital self-image, a rational-empirical approach was recently applied in the development of a new 7-item scale called the FGSIS.


Herbenick D, Schick V, Reece M, Sanders S, Dodge B, Fortenberry JD. The Female Genital Self-Image Scale (FGSIS): Results from a Nationally Representative Probability Sample of Women in the United States. The Journal of Sexual Medicine 2011;8(1):158-66. The Female Genital Self-Image Scale (FGSIS): Resul... [J Sex Med. 2011] - PubMed result

Introduction. Over the past two decades, an expanding body of research has examined women's and men's genital self-image. Support for the reliability and validity of the 7-item Female Genital Self-Image Scale (FGSIS) has been found in a convenience sample of women.

Aims. The purpose of this study was to assess the reliability and validity of the FGSIS, its model of fit, and its association with women's scores on the Female Sexual Function Index (FSFI) in a nationally representative probability sample of women in the United States ages 18 to 60. A second purpose was to assess the temporal stability of the scale in a subset of this sample.

Methods. A nationally representative sample of 3,800 women ages 18 to 60 were invited to participate in a cross-sectional Internet-based survey; 2,056 (54.1%) participated.

Main Demographic items (e.g., age, race/ethnicity, marital?Outcome Measures. status, sexual orientation, geographic region), having had a gynecological examination in the past year, having performed a genital self-examination in the past month, frequency of masturbation in the past month, vibrator use in the past month, the FGSIS, and the FSFI.

Results. An abbreviated 4-item version of the scale, the FGSIS-4, was a better fit to the data than the original 7-item scale. Women's scores on the FGSIS-4 were significantly related to vibrator use, frequency of masturbation, having had a gynecological exam in the past year, having performed genital self examination in the past month, and all FSFI subscales.

Conclusion. Most of the participants felt generally positively about their genitals and female genital self-image was significantly related to female sexual function, women's sexual behavior and their sexual and genital healthcare behaviors. In addition, the FGSIS-4 has evidence of reliability, validity, and temporal stability in a nationally representative probability sample of women in the United States.

 

[Michael Scally MD]

The last decade has seen a surge in research in biomarkers for Alzheimer disease (AD) and other dementia disorders. With predictions of 1 in 4 persons ultimately developing the disease, disorders causing dementia have become one of the major health concerns in aging societies. Impending costs to society and individuals, as well as the enormous and increasing market potential to industry, make this an extremely important field in which the stakes, pressure, and expectations are high to develop better means to establish presence of disease, monitor progression, and make a diagnosis. In that arena, it is of the utmost importance that biomarkers are evaluated in a valid and rigorous way. Two studies in this issue of JAMA report on possible biomarkers for AD and cognitive decline. Both suggest a promising perspective that biomarkers can be developed and found to enable more accurate and earlier diagnosis of neurodegenerative diseases. At the same time, both illustrate that there is room for improvement when it comes to critical aspects of study design and analysis in biomarker evaluation. [Breteler MMB. Mapping Out Biomarkers for Alzheimer Disease. JAMA: The Journal of the American Medical Association 2011;305(3):304-5. Mapping Out Biomarkers for Alzheimer Disease, January 19, 2011, Breteler 305 (3): 304 — JAMA ]


Yaffe K, Weston A, Graff-Radford NR, et al. Association of Plasma Beta-Amyloid Level and Cognitive Reserve With Subsequent Cognitive Decline. JAMA: The Journal of the American Medical Association 2011;305(3):261-6. Association of Plasma ?-Amyloid Level and Cognitive Reserve With Subsequent Cognitive Decline, January 19, 2011, Yaffe et al. 305 (3): 261 — JAMA

Context Lower plasma ?-amyloid 42 and 42/40 levels have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among elders without dementia.

Objective To determine if plasma ?-amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve.

Design, Setting, and Participants We studied 997 black and white community-dwelling older adults from Memphis, Tennessee, and Pittsburgh, Pennsylvania, who were enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998 with 10-year follow-up in 2006-2007. Participant mean age was 74.0 (SD, 3.0) years; 55.2% (n = 550) were female; and 54.0% (n = 538) were black.

Main Outcome Measures Association of near-baseline plasma ?-amyloid levels (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Examination (3MS) results.

Results Low ?-amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (lowest ?-amyloid tertile: mean change in 3MS score, ?6.59 [95% confidence interval [CI], ?5.21 to ?7.67] points; middle tertile: ?6.16 [95% CI, ?4.92 to ?7.32] points; and highest tertile: ?3.60 [95% CI, ?2.27 to ?4.73] points; P < .001). Results were similar after multivariate adjustment for age, race, education, diabetes, smoking, and apolipoprotein E [APOE ] e4 status and after excluding the 72 participants with incident dementia. Measures of cognitive reserve modified this association whereby among those with high reserve (at least a high school diploma, higher than sixth-grade literacy, or no APOE e4 allele), ?-amyloid 42/40 was less associated with multivariate adjusted 9-year decline. For example, among participants with less than a high school diploma, the 3MS score decline was ?8.94 (95% CI, ?6.94 to ?10.94) for the lowest tertile compared with ?4.45 (95% CI, ?2.31 to ?6.59) for the highest tertile, but for those with at least a high school diploma, 3MS score decline was ?4.60 (95% CI,?3.07 to ?6.13) for the lowest tertile and ?2.88 (95% CI,?1.41 to ?4.35) for the highest tertile (P = .004 for interaction). Interactions were also observed for literacy (P = .005) and for APOE e4 allele (P = .02).

Conclusion Lower plasma ?-amyloid 42/40 is associated with greater cognitive decline among elderly persons without dementia over 9 years, and this association is stronger among those with low measures of cognitive reserve.


Clark CM, Schneider JA, Bedell BJ, et al. Use of Florbetapir-PET for Imaging Beta-Amyloid Pathology. JAMA: The Journal of the American Medical Association 2011;305(3):275-83. Sign In — JAMA

Context The ability to identify and quantify brain ?-amyloid could increase the accuracy of a clinical diagnosis of Alzheimer disease.

Objective To determine if florbetapir F 18 positron emission tomographic (PET) imaging performed during life accurately predicts the presence of ?-amyloid in the brain at autopsy.

Design, Setting, and Participants Prospective clinical evaluation conducted February 2009 through March 2010 of florbetapir-PET imaging performed on 35 patients from hospice, long-term care, and community health care facilities near the end of their lives (6 patients to establish the protocol and 29 to validate) compared with immunohistochemistry and silver stain measures of brain ?-amyloid after their death used as the reference standard. PET images were also obtained in 74 young individuals (18-50 years) presumed free of brain amyloid to better understand the frequency of a false-positive interpretation of a florbetapir-PET image.

Main Outcome Measures Correlation of florbetapir-PET image interpretation (based on the median of 3 nuclear medicine physicians' ratings) and semiautomated quantification of cortical retention with postmortem ?-amyloid burden, neuritic amyloid plaque density, and neuropathological diagnosis of Alzheimer disease in the first 35 participants autopsied (out of 152 individuals enrolled in the PET pathological correlation study).

Results Florbetapir-PET imaging was performed a mean of 99 days (range, 1-377 days) before death for the 29 individuals in the primary analysis cohort. Fifteen of the 29 individuals (51.7%) met pathological criteria for Alzheimer disease. Both visual interpretation of the florbetapir-PET images and mean quantitative estimates of cortical uptake were correlated with presence and quantity of ?-amyloid pathology at autopsy as measured by immunohistochemistry (Bonferroni ?, 0.78 [95% confidence interval, 0.58-0.89]; P <.001]) and silver stain neuritic plaque score (Bonferroni ?, 0.71 [95% confidence interval, 0.47-0.86]; P <.001). Florbetapir-PET images and postmortem results rated as positive or negative for ?-amyloid agreed in 96% of the 29 individuals in the primary analysis cohort. The florbetapir-PET image was rated as amyloid negative in the 74 younger individuals in the nonautopsy cohort.

Conclusions Florbetapir-PET imaging was correlated with the presence and density of ?-amyloid. These data provide evidence that a molecular imaging procedure can identify ?-amyloid pathology in the brains of individuals during life. Additional studies are required to understand the appropriate use of florbetapir-PET imaging in the clinical diagnosis of Alzheimer disease and for the prediction of progression to dementia.