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[Michael Scally MD]

Casarini L, Lispi M, Longobardi S, et al. LH and hCG Action on the Same Receptor Results in Quantitatively and Qualitatively Different Intracellular Signalling. PLoS ONE 2012;7(10):e46682. PLOS ONE: LH and hCG Action on the Same Receptor Results in Quantitatively and Qualitatively Different Intracellular Signalling

Human luteinizing hormone (hLH) and chorionic gonadotropin (hCG) act on the same receptor (LHCGR) but it is not known whether they elicit the same cellular and molecular response. This study compares for the first time the activation of cell-signalling pathways and gene expression in response to hLH and hCG.

Using recombinant hLH and recombinant hCG we evaluated the kinetics of cAMP production in COS-7 and hGL5 cells permanently expressing LHCGR (COS-7/LHCGR, hGL5/LHCGR), as well as cAMP, ERK1/2, AKT activation and progesterone production in primary human granulosa cells (hGLC). The expression of selected target genes was measured in the presence or absence of ERK- or AKT-pathways inhibitors.

In COS-7/LHCGR cells, hCG is 5-fold more potent than hLH (cAMP ED50: 107.1±14.3 pM and 530.0±51.2 pM, respectively). hLH maximal effect was significantly faster (10 minutes by hLH; 1 hour by hCG). In hGLC continuous exposure to equipotent doses of gonadotropins up to 36 hours revealed that intracellular cAMP production is oscillating and significantly higher by hCG versus hLH. Conversely, phospho-ERK1/2 and -AKT activation was more potent and sustained by hLH versus hCG. ERK1/2 and AKT inhibition removed the inhibitory effect onNRG1 (neuregulin) expression by hLH but not by hCG; ERK1/2 inhibition significantly increased hLH- but not hCG-stimulated CYP19A1 (aromatase) expression.

We conclude that: i) hCG is more potent on cAMP production, while hLH is more potent on ERK and AKT activation; ii) hGLC respond to equipotent, constant hLH or hCG stimulation with a fluctuating cAMP production and progressive progesterone secretion; and iii) the expression of hLH and hCG target genes partly involves the activation of different pathways depending on the ligand. Therefore, the LHCGR is able to differentiate the activity of hLH and hCG.

 

[Michael Scally MD]

Shaeer O, Shaeer K. The Global Online Sexuality Survey (GOSS): The United States of America in 2011. Chapter I: Erectile Dysfunction Among English-Speakers. The Journal of Sexual Medicine. The Global Online Sexuality Survey (GOSS): The United States of America in 2011. Chapter I: Erectile Dysfunction Among English-Speakers - Shaeer - 2012 - The Journal of Sexual Medicine - Wiley Online Library

Introduction.? The Global Online Sexuality Survey (GOSS) is a worldwide epidemiologic study of sexuality and sexual disorders, based on validated questionnaires and applying age adjustment to the World Standard Population (WSP) by the World Health Organization. In 2010, the first report of GOSS came from the Middle East, describing an erectile dysfunction (ED) prevalence rate of 47%.

Aim.? This report studies the prevalence rate of ED in the United States as of 2011–2012 and evaluates risk factors for ED.

Main Outcome Measures.? Prevalence of ED.

Methods.? GOSS was randomly deployed to English-speaking male web surfers in the United States via paid advertising on Facebook, comprising 146 questions including the abbreviated 5-item International Index of Erectile Function.

Results.? Two thousand twenty-two males participated; with a mean age was 52.38 years ± 14.5. Prevalence of ED was 37.7%, adjusted to 33.7% according to WSP, comparable across ethnic groups. The following risk factors were associated with higher risk for ED: diabetes mellitus, hypertension with and without antihypertensive treatment, coronary heart disease, obesity (defined by body mass index), difficult micturition, subjectively reported depression, interpersonal distress, subjectively reported impotence, in addition to novel factors such as subjectively reported premature ejaculation (PE) and concerns over genital size (not a smaller penis per se), low libido, and irregular coitus. Frequency of smoking and alcohol were not associated with higher prevalence of ED, although duration of smoking was.

Conclusion.? Adjusted to WSP, prevalence rate of ED in the United States of America is 33.7% in the year 2011, in contrast to the adjusted prevalence in the Middle East (47%). Most of the classical risk factors for ED play the same role in the United States and the World, including diabetes, hypertension, and aging. Concerns over genital size and PE are emerging risk factors for ED.

 

[Michael Scally MD]

Hu SC, Ye J, Fathi AK, et al. Mutations in NR5A1 and PIN1 associated with idiopathic hypogonadotropic hypogonadism. Genet Mol Res 2012;11(AOP). http://www.geneticsmr.com//year2012/vol11-4/pdf/gmr2019.pdf

We tested the hypothesis that mutations in NR5A1 and PIN1 cause disorders gonadotropin-gonadal system development and function, throught direct DNA sequencing of the coding sequence and splice-sites of NR5A1 and PIN1 in 50 subjects with sporadic idiopathic hypogonadotropic hypogonadism. These patients were recruited from the Pediatrics section of Tongji Hospital, Tongji Medical College, in Wuhan, China. None of the affected subjects had clinical signs of adrenal insufficiency. The NR5A1 and PIN1 mutations were found in 7 out of 50 cases. These 7 individuals presented with severely low serum concentrations of testosterone or of estradiol and gonadotropin. Adrenal insufficiency was not diagnosed in any of these patients. Consequently NR5A1 or PIN1 mutations should be considered in idiopathic hypogonadotropic hypogonadism patients with normal karyotypes and without adrenal insufficiency.

 

[Michael Scally MD]

Chin KY, Soelaiman IN, Mohamed IN, et al. Testosterone is associated with age-related changes in bone health status, muscle strength and body composition in men. Aging Male. An Error Occurred Setting Your User Cookie

Objective: Variations in testosterone levels are associated with several outcomes of aging. The present study aimed to examine the relationship between age-related decline of testosterone levels and changes in bone health status, handgrip strength, body fat percentage and fat-free mass.

Materials and methods: A total of 335 Malaysian Chinese and Malay men aged 40 years and above were recruited for this study. Their body compositions, calcaneal speed of sound and handgrip strength were measured and their blood was collected. Linear regression analysis was done to examine the relationship among age, testosterone levels and outcomes of aging.

Results: The results indicated significant changes in all testosterone measurements, sex hormone binding globulin level, calcaneal speed of sound, handgrip strength, body fat percentage and fat-free mass with age (p < 0.05). Age-dependent decline in bioavailable and free testosterone levels were significantly associated with reduction in calcaneal speed of sound, fat-free mass and handgrip strength (p < 0.05). Age-dependent decline in the total testosterone level was significantly associated with an increase in body fat percentage among the elderly men (p < 0.05).

Conclusion: Testosterone levels are associated with changes in outcome of aging such as bone health status, muscle strength and body composition, and the relationships are age-dependent.

 

[Michael Scally MD]

Joosten MM, Pai JK, Bertoia ML, et al. Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. JAMA 2012;308(16):1660-7. JAMA Network | JAMA: The Journal of the American Medical Association | Associations Between Conventional Cardiovascular Risk Factors and Risk of Peripheral Artery Disease in MenRisk of Peripheral Artery Disease in Men

CONTEXT: Previous studies have examined the associations of individual clinical risk factors with risk of peripheral artery disease (PAD), but the combined effects of these risk factors are largely unknown.

OBJECTIVE: To estimate the degree to which the 4 conventional cardiovascular risk factors of smoking, hypertension, hypercholesterolemia, and type 2 diabetes are associated with the risk of PAD among men.

DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 44,985 men in the United States without a history of cardiovascular disease at baseline in 1986; participants in the Health Professionals Follow-up Study were followed up for 25 years until January 2011. The presence of risk factors was updated biennially during follow-up.

MAIN OUTCOME MEASURE: Clinically significant PAD defined as limb amputation or revascularization, angiogram reporting vascular obstruction of 50% or greater, ankle-brachial index of less than 0.90, or physician-diagnosed PAD.

RESULTS: During a median follow-up of 24.2 years (interquartile range, 20.8-24.7 years), there were 537 cases of incident PAD. Each risk factor was significantly and independently associated with a higher risk of PAD after adjustment for the other 3 risk factors and confounders. The age-adjusted incidence rates were 9 (95% CI, 6-14) cases/100,000 person-years (n = 19 incident cases) for 0 risk factors, 23 (95% CI, 18-28) cases/100,000 person-years (n = 99 incident cases) for 1 risk factor, 47 (95% CI, 39-56) cases/100,000 person-years (n = 176 incident cases) for 2 risk factors, 92 (95% CI, 76-111) cases/100,000 person-years (n = 180 incident cases) for 3 risk factors, and 186 (95% CI, 141-246) cases/100,000 person-years (n = 63 incident cases) for 4 risk factors. The multivariable-adjusted hazard ratio for each additional risk factor was 2.06 (95% CI, 1.88-2.26). Men without any of the 4 risk factors had a hazard ratio of PAD of 0.23 (95% CI, 0.14-0.36) compared with all other men in the cohort. In 96% of PAD cases (95% CI, 94%-98%), at least 1 of the 4 risk factors was present at the time of PAD diagnosis. The population-attributable risk associated with these 4 risk factors was 75% (95% CI, 64%-87%). The absolute incidence of PAD among men with all 4 risk factors was 3.5/1000 person-years.

CONCLUSION: Among men in this cohort, smoking, hypertension, hypercholesterolemia, and type 2 diabetes account for the majority of risk associated with development of clinically significant PAD.

 

[Michael Scally MD]

Boonen S, Reginster J-Y, Kaufman J-M, et al. Fracture Risk and Zoledronic Acid Therapy in Men with Osteoporosis. New England Journal of Medicine 2012;367(18):1714-23. MMS: Error

BACKGROUND - Fractures in men are a major health issue, and data on the antifracture efficacy of therapies for osteoporosis in men are limited. We studied the effect of zoledronic acid on fracture risk among men with osteoporosis.

METHODS - In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1199 men with primary or hypogonadism-associated osteoporosis who were 50 to 85 years of age to receive an intravenous infusion of zoledronic acid (5 mg) or placebo at baseline and at 12 months. Participants received daily calcium and vitamin D supplementation. The primary end point was the proportion of participants with one or more new morphometric vertebral fractures over a period of 24 months.

RESULTS - The rate of any new morphometric vertebral fracture was 1.6% in the zoledronic acid group and 4.9% in the placebo group over the 24-month period, representing a 67% risk reduction with zoledronic acid (relative risk, 0.33; 95% confidence interval, 0.16 to 0.70; P=0.002). As compared with men who received placebo, men who received zoledronic acid had fewer moderate-to-severe vertebral fractures (P=0.03) and less height loss (P=0.002). Fewer participants who received zoledronic acid had clinical vertebral or nonvertebral fractures, although this difference did not reach significance because of the small number of fractures. Bone mineral density was higher and bone-turnover markers were lower in the men who received zoledronic acid (P<0.05 for both comparisons). Results were similar in men with low serum levels of total testosterone. The zoledronic acid and placebo groups did not differ significantly with respect to the incidence of death (2.6% and 2.9%, respectively) or serious adverse events (25.3% and 25.2%).

CONCLUSIONS - Zoledronic acid treatment was associated with a significantly reduced risk of vertebral fracture among men with osteoporosis.

 

[Michael Scally MD]

Greenspan MB, Barkin J. Erectile dysfunction and testosterone deficiency syndrome: the "portal to men's health". Can J Urol 2012;19(5 Suppl 1):18-27. http://www.canjurol.com/html/free-articles/V19I5S1F-04-DrGreenspan.pdf

Erectile dysfunction (ED) and testosterone deficiency syndrome (TDS) are closely related. In addition to affecting men's sexual health, both conditions also affect other male health issues. Screening for ED, especially in younger men, should become standard clinical practice for the primary care physician. Possible systemic effects and associated effects of TDS are now well documented. Testosterone replacement therapy (TRT) is very safe and effective in the right man.

 

[Michael Scally MD]

Testosterone Regulation Of Akt/mTORC1/FoxO3a Signaling in Skeletal Muscle

Highlights

? Testosterone loss suppresses myofibrillar protein synthesis and Akt/mTOR signaling.
? Suppression of mTORC1 is independent of AMPK activation and Raptor phosphorylation.
? Testosterone loss activates muscle FoxO3a and its transcriptional targets.
? Androgen administration restores Akt/mTORC1/FoxO3a signaling in castrated mice.
? In C2C12 myotubes, testosterone can increase mTORC1 independent of Akt activation.
? 24hr T withdrawal amplifies the activation of Akt/mTORC1 after acute T stimulation.


White JP, Gao S, Puppa MJ, Sato S, Welle SL, Carson JA. Testosterone regulation of Akt/mTORC1/FoxO3a Signaling in Skeletal Muscle. Mol Cell Endocrinol. ScienceDirect.com - Molecular and Cellular Endocrinology - Testosterone regulation of Akt/mTORC1/FoxO3a Signaling in Skeletal Muscle

Low endogenous testosterone production, known as hypogonadism is commonly associated with conditions inducing muscle wasting. Akt signaling can control skeletal muscle mass through mTOR regulation of protein synthesis and FoxO regulation of protein degradation, and this pathway has been previously identified as a target of androgen signaling. However, the testosterone sensitivity of Akt/mTOR signaling requires further understanding in order to grasp the significance of varied testosterone levels seen with wasting disease on muscle protein turnover regulation.

Therefore, the purpose of this study is to determine the effect of androgen availability on muscle Akt/mTORC1/FoxO3a regulation in skeletal muscle and cultured C(2)C(12) myotubes. C57BL/6 mice were either castrated for 42 days or castrated and treated with the nandrolone decanoate (ND) (6 mg/kg bw/wk).

Testosterone loss (TL) significantly decreased volitional grip strength, body weight, and gastrocnemius (GAS) muscle mass, and ND reversed these changes. Related to muscle mass regulation, TL decreased muscle IGF-1 mRNA, the rate of myofibrillar protein synthesis, Akt phosphorylation, and the phosphorylation of Akt targets, GSK3beta, PRAS40 and FoxO3a. TL induced expression of FoxO transcriptional targets, MuRF1, atrogin1 and REDD1. Muscle AMPK and raptor phosphorylation, mTOR inhibitors, were not altered by low testosterone. ND restored IGF-1 expression and Akt/mTORC1 signaling while repressing expression of FoxO transcriptional targets.

Testosterone (T) sensitivity of Akt/mTORC1 signaling was examined in C(2)C(12) myotubes, and mTOR phosphorylation was induced independent of Akt activation at low T concentrations, while a higher T concentration was required to activate Akt signaling. Interestingly, low concentration T was sufficient to amplify myotube mTOR and Akt signaling after 24h of T withdrawal, demonstrating the potential in cultured myotubes for a T initiated positive feedback mechanism to amplify Akt/mTOR signaling.

In summary, androgen withdrawal decreases muscle myofibrillar protein synthesis through Akt/mTORC1 signaling, which is independent of AMPK activation, and readily reversible by anabolic steroid administration. Acute Akt activation in C(2)C(12) myotubes is sensitive to a high concentration of testosterone, and low concentrations of testosterone can activate mTOR signaling independent of Akt.

 

[Michael Scally MD]

Sesso HD, Christen WG, Bubes V, et al. Multivitamins in the Prevention of Cardiovascular Disease in Men: The Physicians' Health Study II Randomized Controlled Trial. JAMA. 2012;308(17):1751-1760. JAMA Network | JAMA: The Journal of the American Medical Association | Multivitamins in the Prevention of Cardiovascular Disease in MenThe Physicians' Health Study II Randomized Controlled TrialMultivitamins in Prevention of CVD in Men

Context Although multivitamins are used to prevent vitamin and mineral deficiency, there is a perception that multivitamins may prevent cardiovascular disease (CVD). Observational studies have shown inconsistent associations between regular multivitamin use and CVD, with no long-term clinical trials of multivitamin use.

Objective To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men.

Design, Setting, and Participants The Physicians' Health Study II, a randomized, double-blind, placebo-controlled trial of a common daily multivitamin, began in 1997 with continued treatment and follow-up through June 1, 2011. A total of 14 641 male US physicians initially aged 50 years or older (mean, 64.3 [SD, 9.2] years), including 754 men with a history of CVD at randomization, were enrolled.

Intervention Daily multivitamin or placebo.

Main Outcome Measures Composite end point of major cardiovascular events, including nonfatal myocardial infarction (MI), nonfatal stroke, and CVD mortality. Secondary outcomes included MI and stroke individually.

Results During a median follow-up of 11.2 (interquartile range, 10.7-13.3) years, there were 1732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (11.0 and 10.8 events per 1000 person-years for multivitamin vs placebo, respectively; hazard ratio

---

, 1.01; 95% CI, 0.91-1.10; P = .91). Further, a daily multivitamin had no effect on total MI (3.9 and 4.2 events per 1000 person-years; HR, 0.93; 95% CI, 0.80-1.09; P = .39), total stroke (4.1 and 3.9 events per 1000 person-years; HR, 1.06; 95% CI, 0.91-1.23; P = .48), or CVD mortality (5.0 and 5.1 events per 1000 person-years; HR, 0.95; 95% CI, 0.83-1.09; P = .47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88-1.02; P = .13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P = .62 for interaction).

Conclusion Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up.

 

[Michael Scally MD]

Yu IC, Lin HY, Liu NC, et al. Neuronal Androgen Receptor Regulates Insulin Sensitivity via Suppression of Hypothalamic NF-kappaB-Mediated PTP1B Expression. Diabetes. Neuronal Androgen Receptor Regulates Insulin Sensitivity via Suppression of Hypothalamic NF-?B–Mediated PTP1B Expression

Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice. The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR. Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice. Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-kappaB (NF-kappaB)-mediated induction of protein-tyrosine phosphatase 1B (PTP1B). Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity. The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-kappaB activation. These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity. Pharmacotherapies targeting neuronal AR and NF-kappaB may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism.

 

[Michael Scally MD]

Delemer B, Aubert J-P, Nys P, Landron Fdr, Bouee Sp. An observational study of the initial management of hypothyroidism in France: the ORCHIDÉE study. European Journal of Endocrinology 2012;167(6):817-23. An observational study of the initial management of hypothyroidism in France: the ORCHIDÉE study

Objective To document the initial management of hypothyroidism in France with respect to diagnostic setting, investigations, and therapeutic approach.

Design Observational study of the management by primary care practitioners (PCPs) and endocrinologists of patients diagnosed with, and treated for, hypothyroidism during the enrollment period or the previous 6 months.

Methods A representative sample of PCPs and endocrinologists enrolled up to five consecutive patients and reported sociodemographic, clinical, therapeutic, and laboratory data. Data were submitted at baseline and at the first measurement of TSH after starting the treatment.

Results The analysis population comprised 1255 patients (mean (s.d.) age 52.8 (16.3) years; 84% female). Hypothyroidism was suspected on clinical grounds in 77% of patients, with goiter in 16%. Autoimmune thyroiditis, supported by positive anti-thyroid antibodies, was the most frequent diagnosis (59%), followed by iatrogenic causes (28%), of which thyroidectomy was the most common. The median baseline TSH was 8.6 mIU/l, suggesting a high incidence of subclinical hypothyroidism. Imaging studies were requested in over 75% of patients, with ultrasound performed in 98% and scintigraphy performed in 19% of these patients. Both groups of physicians treated their patients almost exclusively with levothyroxine. Endocrinologists were more likely than PCPs to provide counseling on how to take medication correctly.

Conclusions This observational study of a large cohort of patients with newly diagnosed hypothyroidism in France illustrates current practice and indicates some areas where physician education may be required to optimize adherence to guidelines and cost-effectiveness.

 

[Michael Scally MD]

Kyratsas C, Dalla C, Anderzhanova E, et al. Experimental Evidence for Sildenafil's Action in the Central Nervous System: Dopamine and Serotonin Changes in the Medial Preoptic Area and Nucleus Accumbens During Sexual Arousal. The Journal of Sexual Medicine. Experimental Evidence for Sildenafil's Action in the Central Nervous System: Dopamine and Serotonin Changes in the Medial Preoptic Area and Nucleus Accumbens During Sexual Arousal - Kyratsas - 2012 - The Journal of Sexual Medicine - Wiley Online Libr

Introduction. Sildenafil is the first effective oral treatment for male erectile dysfunction. Although it is generally accepted that its action is peripheral, it has been suggested that it influences central neural pathways that are involved in male sexual arousal. Recently, it was shown that local sildenafil administration enhances extracellular dopamine (DA) in the nucleus accumbens (NAcc).

Aim. The aim of this study was to determine whether sildenafil administration alters dopaminergic and serotonergic activity in the NAcc and the medial preoptic area (mPOA) during a model of sexual arousal.

Methods. An acute (2 days) or chronic (21 days) sildenafil regimen (1 mg/kg) was administered intraperitoneally to male rats. Thirty minutes after the last sildenafil injection, all males were exposed to noncontact erection sessions by the presentation of inaccessible estrous females. Half of the males had previous experience of noncontact sexual encounter and the other half were exposed for the first time.

Main Outcome Measures. Tissue levels of DA and its metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as serotonin (5-HT) and its metabolite 5-HIAA, were measured in the mPOA and NAcc with high-performance liquid chromatography with electrochemical detector. Dopamine ([DOPAC+HVA]/DA) and serotonin (5-HIAA/5-HT) turnovers were also calculated as indices of neurotransmission.

Results. In nontrained males, acute and chronic sildenafil treatment increased DA and 5-HT turnover rates in the mPOA and NAcc. In trained rats, acute sildenafil also increased DA and 5-HT turnover rates in both structures, whereas chronic treatment enhanced 5-HT turnover rate only in the mPOA and DA turnover rate only in the NAcc.

Conclusions. Our data confirm that sildenafil enhances dopaminergic activity in the NAcc, extend these findings to the mPOA and furthermore, reveal sildenafil-induced effects on serotonergic activity in these brain regions as well. Therefore, present findings support an effect of sildenafil on central neural pathways that are involved in the control of sexual arousal.

 

[Michael Scally MD]

Iacono F et al. Testosterone deficiency causes penile fibrosis and organic erectile dysfunction in aging men. Evaluating association among Age, TDS and ED. BMC Surgery 2012;12(Suppl 1):S24. BMC Surgery | Full text | Testosterone deficiency causes penile fibrosis and organic erectile dysfunction in aging men. Evaluating association among Age, TDS and ED

Introduction - We studied the possible correlation between age, testosterone deficiency, cavernosal fibrosis and erectile dysfunction (ED).

Methods - 47 patients with ED were enrolled between September 2010 and October 2011. IIEF-EF score, NPTR test using the Rigiscan method, total and free testosterone levels, and cavernosum biopsy were carried out on all patients. Patients aged 65 or over were defined as Old Age (OA) while patients under 65 were defined Young age (YA). The strength of the relationships found was estimated by Odds Ratio.

Results - 74% of patients with values of over 52% collagen fibers in the corpora cavernosa were found to have organic ED. A significant difference was found in age, percentage of collagen fibers, testosterone levels between patients with Positive Rigiscan (PR) and Negative Rigiscan (NR). Hypotestosteronaemia increased the risk of ED with PR (OR: 21.4, 95% CI: 20.2-22.6) and in both young age patients (OR: 4.3, 95% CI: 2.4-6.2) and old age patients (OR: 15.5, 95% CI: 13.4-17.6). Moreover cavernosal fibrosis increased the risk of ED with PR in both young age patients (OR: 8.2, 95% CI: 6.4-10.0 and old age patients (OR: 24.6, 95% CI: 20.8-28.4).

Conclusions - This study demonstrates a strong association among age, testosterone deficiency, cavernosal fibrosis and ED with PR. Age, testosterone deficiency and cavernosal fibrosis are potentially correctable factors of cavernosal fibrosis and organic ED. Further, prospective studies are needed to evaluate if testosterone treatment, alone or in association with PDE5 inhibitors, may lower the risk of cavernosal fibrosis or decrease the severity the fibrosis in ED patients.

 

[Michael Scally MD]

Fathi AK, Hu S, Fu X, et al. Molecular defects of the GnRH-receptor gene in Chinese patients with idiopathic hypogonadotropic hypogonadism and the severity of hypogonadism. J Pediatr Endocrinol Metab 2012;25(7-8):659-68. Molecular defects of the GnRH-receptor gene in Chinese patients with idiopathic hypogonadotropic hypogonadism and the severity of hypogonadism

BACKGROUND: Human mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene cause normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations.

OBJECTIVES: To identify and determine the frequency of mutations in the coding region of the gonadotropin-releasing hormone receptor (GnRHR) gene in forty Chinese patients with normosmic idiopathic hypogonadotropic hypogonadism (IHH) and establish genotype/phenotype correlations where possible.

METHODS: The diagnosis of HH was based on absent or incomplete sexual development after 17 years of age in girls and 18 years in boys associated with low or normal levels of LH in both sexes and low levels of testosterone in males and of estradiol in females. All patients presented with a normal sense of smell in an olfactory specific test. Forty IHH patients and 40 controls were screened for mutations in the coding sequence of the GnRHR gene. The coding region of the GnRHR gene was amplified by PCR and directly sequenced.

RESULTS: A missense mutation, serine 168 arginine (S168R), located in the fourth transmembrane domain of the GnRHR gene, was identified as being in a homozygous state in one male with complete HH. The S168R mutation has been previously shown to be a cause in the complete loss of receptor function because hormone binding to the receptor is completely impaired. In another patient, a compound heterozygous mutation (Gln106Arg and Arg262Gln) was identified in a male with partial HH. The Gln106Arg mutation is located in the first extracellular loop of GnRH-R, this mutation decreases but not does eliminate GnRH binding; while Arg262Gln mutation is located in the third extracellular loop of GnRH-R and only decreases signal transduction. A good correlation between genotype and phenotype was found in our patients. The patient, who was homozygous for the completely inactivating S168R mutation, had complete HH. In addition, the affected patient who was compound heterozygous for the Glnl06Arg--Arg262Gln mutations - has partial HH.

CONCLUSIONS: GnRHR mutations can be classified into partial or complete loss of function mutations. Partially inactivating substitutions of the GnRHR frequently found in familial hypogonadotrophic hypogonadism are Q106R and R262Q. Comparison of compound heterozygous with homozygous patients suggests that their phenotype and the response to GnRH is determined by the GnRHR variant with the less severe loss of function.

 

[Michael Scally MD]

Rogers JH, Goldstein I, Kandzari DE, et al. Zotarolimus-Eluting Peripheral Stents for the Treatment of Erectile Dysfunction in Subjects With Suboptimal Response to Phosphodiesterase-5 Inhibitors. J Am Coll Cardiol. Published online November 21, 2012. American College of Cardiology Foundation | Journal of the American College of Cardiology | Zotarolimus-Eluting Peripheral Stents for the Treatment of Erectile Dysfunction in Subjects With Suboptimal Response to Phosphodiesterase-5 Inhibitors

Objectives This study sought to evaluate the safety and feasibility of zotarolimus-eluting stent implantation in focal atherosclerotic lesions of the internal pudendal arteries among men with erectile dysfunction (ED) and a suboptimal response to phosphodiesterase-5 inhibitors.

Background ED, a common condition, is often mediated by atherosclerosis. Current treatment options are limited.

Methods Male subjects with atherosclerotic ED and a suboptimal response to phosphodiesterase-5 inhibitors were enrolled in this prospective, multicenter, single-armed safety and feasibility trial. A novel combination of clinical, duplex ultrasound, and invasive angiographic factors were used to determine eligibility for stent therapy. The primary safety endpoint was any major adverse event 30 days after the procedure. The primary feasibility end point was improvement in the International Index of Erectile Function (Erectile Dysfunction Domain) score ?4 points in ?50% of subjects at 3 months. We report 6-month follow-up results, including duplex ultrasound and angiography.

Results Forty-five lesions were treated with stents in 30 subjects. Procedural success was 100% with no major adverse events through follow-up. The primary feasibility endpoint at 6 months was achieved by 59.3% of intention-to-treat subjects (95% confidence interval: 38.8% to 77.6%) and 69.6% of per-protocol subjects (95% confidence interval: 47.1% to 86.8%). Duplex ultrasound peak systolic velocity of the cavernosal arteries increased from baseline by 14.4 ± 10.7 cm/s at 30 days and 22.5 ± 23.7 cm/s at 6 months. Angiographic binary restenosis (?50% lumen diameter stenosis) was reported in 11 (34.4%) of 32 lesions.

Conclusions Among patients with ED and limited response with pharmacologic therapy, percutaneous stent revascularization of the internal pudendal artery is feasible and is associated with clinically meaningful improvement in both subjective and objective measures of erectile function.

 

[Michael Scally MD]

Haring R, John U, Volzke H, et al. Low Testosterone Concentrations in Men Contribute to the Gender Gap in Cardiovascular Morbidity and Mortality. Gend Med. ScienceDirect.com - Gender Medicine - Low Testosterone Concentrations in Men Contribute to the Gender Gap in Cardiovascular Morbidity and Mortality

BACKGROUND: Across the industrialized world, men experience an earlier onset of cardiovascular disease (CVD) and a life expectancy 5 to 10 years shorter than women. Low total testosterone (TT) concentrations in men have been suggested as a novel CVD risk factor, but its contribution to this gender gap is less well studied.

METHODS: We used data of 4152 individuals (2113 women and 2039 men) aged 20 to 79 years from the longitudinal population-based cohort Study of Health in Pomerania, Germany. Multivariable Poisson and Cox proportional hazard regression models were used to investigate the risk of incident cardiovascular morbidity (5-year examination follow-up), as well as all-cause and CVD mortality (10-year follow-up) between men and women. Additionally, the added risk attributable to low TT in men (<10th percentile) was assessed.

RESULTS: Compared with women, men were uniformly at higher risk of incident cardiovascular morbidity, including overweight, hypertension, dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. Men were also at increased all-cause mortality (hazard ratio = 2.05; 95% CI, 1.61-2.60) and 10-year CVD risk compared with women. In subgroup analyses, men with low TT showed the highest 10-year CVD and mortality risk compared with both men with higher TT and women. TT was also negatively associated with cardiovascular risk as defined by the Framingham risk score (P < 0.001), after multivariable adjustment.

CONCLUSIONS: Analyzing a large population-based sample, we observed that men have a generally higher risk of incident cardiovascular morbidity and mortality. Furthermore, men with low TT concentrations were identified as high-risk individuals with regard to 10-year CVD and mortality risk.

 

[Michael Scally MD]

Kweon SS, Shin MH, Nam HS, et al. Sex Differences in the Associations of Testosterone and Sex Hormone-Binding Globulin With Metabolic Syndrome in Middle-Aged and Elderly Koreans. Circ J. https://www.jstage.jst.go.jp/article/circj/advpub/0/advpub_CJ-12-0613/_pdf

Background: We investigated the sex-dependent associations of testosterone and sex hormone-binding globulin (SHBG) levels with metabolic syndrome (MetS).

Methods and Results: We conducted a cross-sectional study of 9,424 community-dwelling adults aged 45-74 years (median age, 63.7 years). MetS was defined according to the updated version of the National Cholesterol Education Program Adult Treatment Panel III criteria. Serum total testosterone (TT) and SHBG levels were determined using a chemiluminescent microparticle immunoassay, and free testosterone (FT) concentrations were calculated. In a multivariate analysis, TT levels were inversely associated with MetS in men (odds ratio [OR] of each standard deviation increase in the logarithmic value, 0.70; 95% confidence interval [CI], 0.65-0.76), whereas they were positively associated in women (OR, 1.17; 95% CI, 1.10-1.24). FT levels were positively associated with MetS in women only (OR, 1.39; 95% CI, 1.30-1.49). However, SHBG levels were negatively associated with MetS in both men (OR, 0.57; 95% CI, 0.52-0.61) and women (OR, 0.61; 95% CI, 0.57-0.66).

Conclusions: Our data showed that higher TT levels were associated with a reduced prevalence of MetS in men and an elevated prevalence of MetS in women. Higher SHBG levels were associated with decreased prevalence of MetS in both sexes. These results suggest sex differences in the associations of endogenous testosterone and SHBG with MetS.

 

[Michael Scally MD]

Botelho JC, Shacklady C, Cooper HC, et al. Isotope-Dilution Liquid Chromatography/Tandem Mass Spectrometry Candidate Reference Method for Total Testosterone in Human Serum. Clin Chem. Isotope-Dilution Liquid Chromatography/Tandem Mass Spectrometry Candidate Reference Method for Total Testosterone in Human Serum

BACKGROUND: We developed and evaluated a candidate reference measurement procedure (RMP) to standardize testosterone measurements, provide highly accurate and precise value assignments for the CDC Hormone Standardization Program, and ensure accurate and comparable results across testing systems and laboratories.

METHODS: After 2 liquid/liquid extractions of serum with a combination of ethyl acetate and hexane, we quantified testosterone by isotope-dilution liquid chromatography/tandem mass spectrometry with electrospray ionization in the positive ion mode monitoring 289-->97 m/z (testosterone) and 292-->112 m/z ((3)C(13) testosterone). We used calibrator bracketing and gravimetric measurements to give higher specificity and accuracy to serum value assignments. The candidate RMP was evaluated for accuracy by use of NIST-certified reference material SRM971 and validated by split-sample comparison to established RMPs. We evaluated intraassay and interassay imprecision, measurement uncertainty, potential interferences, and matrix effects.

RESULTS: A weighted Deming regression comparison of the candidate RMP to established RMPs showed agreement with no statistical difference (slope 0.99, 95% CI 0.98-1.00, intercept 0.54, 95% CI -1.24 to 2.32) and a bias of </=0.3% for NIST SRM971. The candidate RMP gave maximum intraassay, interassay, and total percent CVs of 1.5%, 1.4%, and 1.7% across the concentrations of testosterone typically found in healthy men and women. We tested structural analogs of testosterone and 125 serum samples and found no interferences with the measurement.

CONCLUSIONS: This RMP for testosterone can serve as a higher-order standard for measurement traceability and can be used to provide an accuracy base to which routine methods can be compared in the CDC Hormone Standardization Program.

 

[Michael Scally MD]

Garber JR, Cobin RH, Gharib H, et al. Clinical Practice Guidelines for Hypothyroidism in Adults: Co-sponsored by American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 2012. https://www.aace.com/files/hypothyroidism_guidelines.pdf

Background: Hypothyroidism has multiple etiologies and manifestations. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions. This paper describes evidence-based clinical guidelines for the clinical management of hypothyroidism in ambulatory patients.

Methods: The development of these guidelines was commissioned by the American Association of Clinical Endocrinologists (AACE) in association with American Thyroid Association (ATA). AACE and the ATA assembled a task force of expert clinicians who authored this report. The authors examined relevant literature and took an evidence-based medicine approach that incorporated their knowledge and experience to develop a series of specific recommendations and the rationale for these recommendations. The strength of the recommendations and the quality of evidence supporting each was rated according to the approach outlined in the American Association of Clinical Endocrinologists Protocol for Standardized Production of Clinical Guidelines-2010 update.

Results: Topics addressed include the etiology, epidemiology, clinical and laboratory evaluation, management, and consequences of hypothyroidism. Screening, treatment of subclinical hypothyroidism, pregnancy, and areas for future research are also covered.

Conclusions: Fifty two evidence-based recommendations were developed to aid in the care of patients with hypothyroidism and to share what the authors believe is current, rational and optimal medical practice for the diagnosis and care of hypothyroidism. A serum TSH is the single best screening test for primary thyroid dysfunction for the vast majority of outpatient clinical situations. The standard treatment is replacement with L-thyroxine (T4). The decision to treat subclinical hypothyroidism, when the serum TSH is less than 10 mIU/L, should be tailored to the individual patient.


Vaidya B. Thyroid function: New guidelines for the management of hypothyroidism. Nat Rev Endocrinol 2012;9(1):11-2. http://www.nature.com/nrendo/journal/v9/n1/full/nrendo.2012.226.html

 

[Michael Scally MD]

Zhu CC, Zhang H, Zhang JS, et al. Inhibition of ghrelin signaling improves the reproductive phenotype of male ob/ob mouse. Fertil Steril. ScienceDirect.com - Fertility and Sterility - Inhibition of ghrelin signaling improves the reproductive phenotype of male ob/ob mouse

OBJECTIVE: To investigate whether ghrelin signaling is involved in the pathogenesis of male factor infertility induced by leptin deficiency.

DESIGN: Experimental study. SETTING: University academic medical center. ANIMAL(S): Ten-week-old C57BL/6J mice and ob/ob mice.

INTERVENTION(S): Western blotting, (quantitative) reverse transcription-polymerase chain reaction (qRT-PCR), immunohistochemistry, and in situ end labeling of fragmented DNA.

MAIN OUTCOME MEASURE(S): Expression levels of ghrelin and its functional receptor growth hormone (GH) secretagogue receptor 1a (GHS-R1alpha) were examined by Western blotting and immunohistochemistry. Ob/ob mice were injected IP with specific GHS-R1alpha antagonist, and thereafter germ cell apoptosis and steroidogenic capability were assessed by TUNEL assay, (q) RT-PCR, and radioimmunoassay.

RESULT(S): Expression of GHS-R1alpha and its endogenous ligand ghrelin was both up-regulated in ob/ob testis. Inhibition of the ghrelin pathway restored androgen synthesis, reduced germ cell apoptosis, and thereby resulted in improved sperm production in ob/ob mice.

CONCLUSION(S): Ghrelin, as an antagonistic partner of leptin in the endocrinic/paracrine circuit, may be involved in the pathogenesis of male factor infertility induced by leptin deficiency.