OnLine First

[Michael Scally MD]

Sirianni R, Capparelli C, Chimento A, et al. Nandrolone and stanozolol upregulate aromatase expression and further increase IGF-I-dependent effects on MCF-7 breast cancer cell proliferation. Mol Cell Endocrinol. ScienceDirect.com - Molecular and Cellular Endocrinology - Nandrolone and stanozolol upregulate aromatase expression and further increase IGF-I-dependent effects on MCF-7 breast cancer cell proliferation

Several doping agents, such as anabolic androgenic steroids (AAS) and peptide hormones like insulin-like growth factor-I (IGF-I), are employed without considering the potential deleterious effects that they can cause. In addition, androgens are used in postmenopausal women as replacement therapy. However, there are no clear guidelines regarding the optimal therapeutic doses of androgens or long-term safety data. In this study we aimed to determine if two commonly used AAS, nandrolone and stanozolol, alone or in combination with IGF-I, could activate signaling involved in breast cancer cell proliferation. Using a human breast cancer cell line, MCF-7, as an experimental model we found that both nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and, consequently, estradiol production. Moreover, when nandrolone and stanozolol were combined with IGF-I, higher induction in aromatase expression was observed. This increase involved phosphatidylinositol 3-kinase (PI3K)/AKT and phospholipase C (PLC)/protein kinase C (PKC), which are part of IGF-I transductional pathways. Specifically, both AAS were able to activate membrane rapid signaling involving IGF-I receptor, extracellular regulated protein kinases 1/2 (ERK1/2) and AKT, after binding to estrogen receptor (ER), as confirmed by the ability of the ER antagonist ICI182, 780 to block such activation. The estrogenic activity of nandrolone and stanozolol was further confirmed by their capacity to induce the expression of the ER-regulated gene, CCND1 encoding for the cell cycle regulator cyclin D1, which represents a key protein for the control of breast cancer cell proliferation. In fact, when nandrolone and stanozolol were combined with IGF-I, they increased cell proliferation to levels higher than those elicited by the single factors. Taken together these data clearly indicate that the use of high doses of AAS, as occurs in doping practice, may increase the risk of breast cancer. This potential risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS with this type of cancer.

 

[Michael Scally MD]

Schmid TE, Eskenazi B, Marchetti F, et al. Micronutrients intake is associated with improved sperm DNA quality in older men. Fertility and Sterility. ScienceDirect.com - Fertility and Sterility - Micronutrients intake is associated

Objective - To investigate whether lifestyle factors such as increased dietary intake of micronutrients reduce the risks of sperm DNA damage, and whether older men benefit more than younger men.

Design - Cross-sectional study design with equalized assignments into age groups.

Setting - National laboratory and university.

Patient(s) - Nonclinical group of 22–80-year-old nonsmoking men (n = 80) who reported no fertility problems.

Main Outcome Measure(s) - Sperm DNA damage measured by alkaline and neutral DNA electrophoresis (i.e., sperm Comet assay).

Result(s) - Sociodemographics, occupational exposures, medical and reproductive histories, and lifestyle habits were determined by questionnaire. The average daily dietary and supplement intake of micronutrients (vitamin C, vitamin E, b-carotene, zinc, and folate) was determined using the 100-item Modified Block Food Frequency Questionnaire (FFQ). Men with the highest intake of vitamin C had approximately 16% less sperm DNA damage (alkaline sperm Comet) than men with the lowest intake, with similar findings for vitamin E, folate, and zinc (but not ?-carotene). Older men (>44 years) with the highest vitamin C intake had approximately 20% less sperm DNA damage compared with older men with the lowest intake, with similar findings for vitamin E and zinc. The older men with the highest intake of these micronutrients showed levels of sperm damage that were similar to those of the younger men. However, younger men (<44 years) did not benefit from higher intakes of the micronutrients surveyed.

Conclusion(s) - Men with higher dietary and supplement intake of certain micronutrients may produce sperm with less DNA damage, especially among older men. This raises the broader question of how lifestyle factors, including higher intakes of antioxidants and micronutrients, might protect somatic as well as germ cells against age-associated genomic damage.

 

[keriheat]

Schmid TE, Eskenazi B, Marchetti F, et al. Micronutrients intake is associated with improved sperm DNA quality in older men. Fertility and Sterility. ScienceDirect.com - Fertility and Sterility - Micronutrients intake is associated

Objective - To investigate whether lifestyle factors such as increased dietary intake of micronutrients reduce the risks of sperm DNA damage, and whether older men benefit more than younger men.

Design - Cross-sectional study design with equalized assignments into age groups.

Setting - National laboratory and university.

Patient(s) - Nonclinical group of 22–80-year-old nonsmoking men (n = 80) who reported no fertility problems.

Main Outcome Measure(s) - Sperm DNA damage measured by alkaline and neutral DNA electrophoresis (i.e., sperm Comet assay).

Result(s) - Sociodemographics, occupational exposures, medical and reproductive histories, and lifestyle habits were determined by questionnaire. The average daily dietary and supplement intake of micronutrients (vitamin C, vitamin E, b-carotene, zinc, and folate) was determined using the 100-item Modified Block Food Frequency Questionnaire (FFQ). Men with the highest intake of vitamin C had approximately 16% less sperm DNA damage (alkaline sperm Comet) than men with the lowest intake, with similar findings for vitamin E, folate, and zinc (but not ?-carotene). Older men (>44 years) with the highest vitamin C intake had approximately 20% less sperm DNA damage compared with older men with the lowest intake, with similar findings for vitamin E and zinc. The older men with the highest intake of these micronutrients showed levels of sperm damage that were similar to those of the younger men. However, younger men (<44 years) did not benefit from higher intakes of the micronutrients surveyed.

Conclusion(s) - Men with higher dietary and supplement intake of certain micronutrients may produce sperm with less DNA damage, especially among older men. This raises the broader question of how lifestyle factors, including higher intakes of antioxidants and micronutrients, might protect somatic as well as germ cells against age-associated genomic damage.

I always wondered why my kids didn't play the violin, or become the track star, or design the 'Delphinburg' building. I guess it was DNA damage. I should have ate my veggies!

 

[Michael Scally MD]

Phongkitkarun S, Rassameepong A, Permpongkosol S, Taphey M, Wibulpolprasert B. Transrectal ultrasound (TRUS) findings of the prostate gland in late onset hypogonadism with testosterone supplementation in correlation with clinical outcome. J Med Assoc Thai 2012;95(7):953-9. Transrectal Ultrasound (TRUS) Findings of the Prostate Gland in Late Onset Hypogonadism with Testosterone Supplementation in Correlation with Clinical Outcome | Phongkitkarun | Journal of the Medical Association of Thailand

OBJECTIVE: To determine the TRUS findings of the prostate and correlation of ultrasoundfindings with clinical outcomes in late-onset hypogonadal (LOH) men with testosterone supplementation.

MATERIAL AND METHOD: Between January 2007 and September 2010, TRUS findings and clinical outcomes of 16 from 226 subjects were studied The demographic data, ultrasound parameters as prostate volume and vascularity, and clinical parameters were evaluated Correlation between ultrasound and clinical parameters were analyzed using Pearson correlation analysis.

RESULTS: During mean time follow-up of 6.48 months, the volume of the central gland (CG) significantly increased (p = 0.02), the volume of the total gland (TG) increased, and the volume of the peripheral zone (PZ) slightly decreased. The vascularity of the TG, CG, and PZ were significantly increased. The periurethral region vascularity was not significantly increased (p = 0.06), whereas total serum testosterone, prostate specific antigen (PSA), and PSA density were increased The International Prostate Symptom Score (IPSS) was significantly decreased (p < 0.001). There was a significant correlation between increased prostate volume and increased serum PSA.

CONCLUSION: Testosterone supplementation in LOH men was found to cause an increase in TG volume during the first six months. The preferentially increased CG volume and prostatic vascularity might be due to exogenous testosterone. The authors observed a significantly increased PSA with a strong correlation between serum PSA and prostate volume.

 

[Michael Scally MD]

Nationwide Emergency Department Visits for Priapism in the United States (#070)
World Meeting on Sexual Medicine - Chicago, USA - August 26-30, 2012

Introduction and Objectives: The true prevalence of priapism is not well characterized. A small number of studies based on inpatient data or small population samples have estimated a prevalence ranging from 0.34 to 1.5 cases per 100,000 males. We set forth to estimate the current epidemiology and impact on resource utilization of priapism in the United States (US).

Methods: Emergency department (ED) visits for priapism were analyzed using discharge data from the Nationwide Emergency Department Sample (NEDS), Healthcare Cost and Utilization Project (HCUP), which contains over 25 million ED records per year, representing a 20% stratified sample of US hospital ED visits. Priapism encounters were identified by ICD9 code and analyzed with patient and hospital characteristics, hospital charge, and length of stay (LOS) if admitted. Established weighting in the sample was used to calculate nationwide estimates.

Results: 4,175 ED encounters for priapism were identified between 2007 and 2008 in the NEDS. This translated to an estimated 18,969 encounters for 2007 and 2008 out of a total of 247,277,003 ED visits, or 7.67 per 100,000 ED visits [95% confidence interval (CI) 6.52- 8.05]. Assuming that all men with priapism would present to an ED, this would estimate a national prevalence of 6.35 encounters per 100,000 male population. The mean age was 36.4 years old. 19.9% of patients had a concurrent diagnosis of sickle cell disease (SCD). 71.6% of all patients were discharged home from the ED, while only 48.8% of patients with SCD were discharged home. Concurrent diagnosis of SCD was associated with an odds ratio (OR) of 3.18 [95% CI of 2.35-4.32] for admission to the hospital when controlling for age, region, hospital and payer type. The mean hospital charge was $1,776 per encounter if discharged home and $44,118 per encounter if admitted.

Conclusions: Approximately three-fourths of all ED presentations for priapism were discharged home from the ED. Concurrent SCD was associated with a 3-fold likelihood of inpatient admission. As expected, inpatient admission was associated with a significantly higher cost. Compared to prior reports on priapism, the current research found a significantly higher prevalence of priapism, and a lower concurrence rate with SCD.

 

[keriheat]

Nationwide Emergency Department Visits for Priapism in the United States (#070)
World Meeting on Sexual Medicine - Chicago, USA - August 26-30, 2012

Introduction and Objectives: The true prevalence of priapism is not well characterized. A small number of studies based on inpatient data or small population samples have estimated a prevalence ranging from 0.34 to 1.5 cases per 100,000 males. We set forth to estimate the current epidemiology and impact on resource utilization of priapism in the United States (US).

Methods: Emergency department (ED) visits for priapism were analyzed using discharge data from the Nationwide Emergency Department Sample (NEDS), Healthcare Cost and Utilization Project (HCUP), which contains over 25 million ED records per year, representing a 20% stratified sample of US hospital ED visits. Priapism encounters were identified by ICD9 code and analyzed with patient and hospital characteristics, hospital charge, and length of stay (LOS) if admitted. Established weighting in the sample was used to calculate nationwide estimates.

Results: 4,175 ED encounters for priapism were identified between 2007 and 2008 in the NEDS. This translated to an estimated 18,969 encounters for 2007 and 2008 out of a total of 247,277,003 ED visits, or 7.67 per 100,000 ED visits [95% confidence interval (CI) 6.52- 8.05]. Assuming that all men with priapism would present to an ED, this would estimate a national prevalence of 6.35 encounters per 100,000 male population. The mean age was 36.4 years old. 19.9% of patients had a concurrent diagnosis of sickle cell disease (SCD). 71.6% of all patients were discharged home from the ED, while only 48.8% of patients with SCD were discharged home. Concurrent diagnosis of SCD was associated with an odds ratio (OR) of 3.18 [95% CI of 2.35-4.32] for admission to the hospital when controlling for age, region, hospital and payer type. The mean hospital charge was $1,776 per encounter if discharged home and $44,118 per encounter if admitted.

Conclusions: Approximately three-fourths of all ED presentations for priapism were discharged home from the ED. Concurrent SCD was associated with a 3-fold likelihood of inpatient admission. As expected, inpatient admission was associated with a significantly higher cost. Compared to prior reports on priapism, the current research found a significantly higher prevalence of priapism, and a lower concurrence rate with SCD.

Epidemiology--Can you say 'GRANT MONEY'. 1 in 100,000 men? Priapism?

I think we could benefit more, if we spent this money on that ' Cow farting study' and tell the guys with the 'Hard-on's' to go easy on the Viagra!

 

[Michael Scally MD]

Lennartsson AK, Kushnir MM, Bergquist J, Jonsdottir IH. DHEA and DHEA-S response to acute psychosocial stress in healthy men and women. Biol Psychol 2012;90(2):143-9. ScienceDirect.com - Biological Psychology - DHEA and DHEA-S response to acute psychosocial stress in healthy men and women

This study investigates the effect of acute psychosocial stress on serum concentrations of DHEA and DHEA-S in healthy men and women. Twenty men and 19 women (age 30-50 years) underwent Trier Social Stress Test (TSST). Physiological measurements were performed before, directly after the stress test and after 30 mins of recovery. In both men and women, significantly elevated DHEA and DHEA-S levels were observed in response to the stressor. There was a large inter-individual variation in the magnitude of the response, especially for DHEA but no statistical difference between men and women. Magnitude of the change in the levels of DHEA was found to be positively associated with the magnitude of the changes in ACTH, cortisol and heart rate. Furthermore, the results of this study suggest that the capacity to secrete DHEA and DHEA-S during acute psychosocial stress declines with age.

 

[Michael Scally MD]

Jin G, Sun J, Kim ST, et al. Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men. Hum Mol Genet. Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men

Circulating androgen levels are often used as indicators of physiological or pathological conditions. More than half of the variance for circulating androgen levels is thought to be genetically influenced. A genome-wide association study (GWAS) has identified two loci, SHBG at 17p13 and FAM9B at Xp22, for serum testosterone (T) levels; however, these explain only a small fraction of inter-individual variability. To identify additional genetic determinants of androgen levels, a genome-wide association study (GWAS) of baseline serum T and dihydrotestosterone (DHT) levels was conducted in 3,225 men of European ancestry from the REduction by DUtasteride of Prostate Cancer Events (REDUCE) study. Cross-validation was used to confirm the observed associations between the drug (n=1,581) and placebo (n=1,644) groups of REDUCE. In addition to confirming the associations of two known loci with serum T levels (rs727428 in SHBG: P=1.26x10(-12); rs5934505 in FAM9B: P=1.61x10(-8)), we identified a new locus, JMJD1C at 10q21 that was associated with serum T levels at a genome-wide significance level (rs10822184: P=1.12x10(-8)). We also observed the SHBG locus was associated with serum DHT levels (rs727428: P=1.47x10(-11)). Moreover, two additional variants in SHBG [rs72829446, in strong linkage equilibrium with the missense variant D356N (rs6259), and rs1799941] were also independently associated with circulating androgen levels in a statistical scale. These three loci (JMJD1C, SHBG and FAM9B) were estimated to account for about 5.3% and 4.1% of the variance of serum T and DHT levels. Our findings may provide new insights into the regulation of circulating androgens and potential targets for androgen-based therapy.

 

[Michael Scally MD]

Gislefoss RE, Grimsrud TK, Hoie K, Morkrid L. Stability of testosterone measured in male archival serum samples by two different methods. Scand J Clin Lab Invest. Stability of testosterone measured in male archival serum samples by two different methods, Scandinavian Journal of Clinical & Laboratory Investigation, Informa Healthcare

Objective. To investigate testosterone stability in archival serum samples stored for etiological cancer research, and compare two methods for testosterone measurements.

Design and measurements. Four sets of 130 serum samples were randomly selected from male blood donors, aged 40-49 years at the time of blood draw. The sets had been stored at -25 degrees C for 1 month, 4, 17 and 29 years, respectively, and were analyzed for testosterone, sex hormone binding globuline, follicle stimulating hormone, luteinizing hormone, sodium, albumin and cotinine. Testosterone was measured by two methods, an electrochemiluminescence immunoassay, and a liquid chromatography tandem mass spectrometry method.

Results. The mean level of testosterone in the samples with the longest storage time (29 years) was substantially higher than that of the fresh samples. The two techniques gave approximately equal results for testosterone values in the range 5-27.5 nmol/L, close to normal range.

Conclusions. The high mean levels of testosterone in the oldest samples suggest a downward trend over the last three decades, as any degradation during storage would tend to give the opposite result. For archival serum samples, both electrochemiluminescence immunoassay and liquid chromatography tandem mass spectrometry are applicable methods for measurement of testosterone within the expected reference range.

 

[Michael Scally MD]

Poggi M, Monti S, Lauri C, Pascucci C, Bisogni V, Toscano V. Primary empty sella and GH deficiency: prevalence and clinical implications. Ann Ist Super Sanita 2012;48(1):91-6. http://www.iss.it/publ/anna/2012/1/48191.pdf

Primary empty sella (PES) is a particular anatomical condition characterized by the herniation of liquor within the sella turcica. The pathogenesis of this alteration, frequently observed in general population, is not yet completely understood. Recently reports demonstrated, in these patients, that hormonal pituitary dysfunctions, specially growth hormone (GH)/insulin- like growth factor (IGF-I) axis ones, could be relevant. The aim of this paper is to evaluate GH/IGF-I axis in a group of adult patients affected by PES and to verify its clinical relevance. We studied a population of 28 patients with a diagnosis of PES. In each patient we performed a basal study of thyroid, adrenal and gonadal - pituitary axis and a dynamic evaluation of GH/IGF-I after GH-releasing hormone (GHRH) plus arginine stimulation test. To evaluate the clinical significance of GH/IGF-I axis dysfunction we performed a metabolic and bone status evaluation in every patients. We found the presence of GH deficit in 11 patients (39.2%). The group that displayed a GH/IGF-I axis dysfunction showed an impairment in metabolic profile and bone densitometry. This study confirms the necessity to screen the pituitary function in patients affected by PES and above all GH/IGF-I axis. Moreover the presence of GH deficiency could be clinically significant.

 

[Michael Scally MD]

Owen LJ, Keevil BG. Testosterone measurement by liquid chromatography tandem mass spectrometry: the importance of internal standard choice. Ann Clin Biochem. Testosterone measurement by liquid chromatography tandem mass spectrometry: the importance of internal standard choice

BACKGROUND: Testosterone measurement by liquid chromatography tandem mass spectrometry (LC-MS/MS) is well accepted as the preferred technique for the analysis of testosterone. Variation is seen between assays and is likely to be due to method differences. One area of inconsistency among assays is the choice of internal standard. We investigated the effects of three internal standards.

METHODS: Testosterone with two deuterium (D2), five deuterium (D5) and three carbon 13 enrichment (C13) were separately assessed. Samples were extracted using ether following the addition of 10 muL of internal standard. All aliquots were prepared in triplicate, one for each type of internal standard. After mixing, the ether was transferred to a 96-deep well block, and then evaporated to dryness. Extracts were reconstituted with 50% mobile phases and analysed using a Waters Acquity UPLC and Quattro Premier tandem mass spectrometer. This method had previously been shown to have excellent agreement with a reference method using the D2 internal standard and this was considered the target.

RESULTS: Lower results were obtained when using D5 testosterone when compared with D2 testosterone. The C13 internal standard also gave lower results, but was closer to the D2 target than the D5 internal standard.

CONCLUSIONS: The choice of internal standard alone can have a significant affect on the results obtained by LC-MS/MS assays for testosterone using this chromatography. The effects of the combination of chromatography and internal standard choice should be investigated during method development.

 

[Michael Scally MD]

[ame=http://www.youtube.com/watch?v=wR0uajiyf-M]JCI's Conversation with Giants in Medicine: Jean Wilson - YouTube[/ame]

 

[Michael Scally MD]

Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on treatment of male testosterone deficiency - a prospective study. Int Braz J Urol 2012;38(4):512-8. :: International Braz J Urol ::

Introduction: Male testosterone deficiency is associated with bad sexual function and quality of life (QoL). The aim of this study was to determine whether a daily dose of 25 mg clomiphene citrate (CC) is effective in stimulating the endogenous testosterone production pathway and to address the applicability of this medication as a therapeutic option for symptomatic hypogonadism.

Materials and Methods: This was a prospective study. Men with low sexual desire and testosterone levels (T) below 400 ng/dL were selected to receive CC. Blood samples were obtained to determine baseline measurements of serum T, estradiol, LH, lipid profile and fasting plasma glucose. Each patient was treated with a daily dose of 25 mg CC for at least 3 months. Patients were asked if they experienced any side effects related to the use of CC and if they experienced any improvement in their sexual profile. Paired samples T-test was utilized to analyze responses to therapy.

Results: Our cohort consisted of 125 men with hypogonadism and low libido. Mean age was 62 years (+/- 11.1 years). Serum T levels ranged from 309 ng/dL (baseline, mean value) to 642 ng/dL (3 months after CC initiation, mean value) (p < 0.001). Serum cholesterol levels ranged from 197 to 186 mg/dL (p = 0.003). There were no statistically significant differences when comparing pre and post-treatment HDL-Cholesterol, triglycerides, fasting plasma glucose and prolactin. All men reported improvements in the post-treatment QoL scores. No serious adverse events were recorded.

Conclusions: The CC was effective in stimulating the endogenous production of testosterone. A lower level of total cholesterol was verified after three months of treatment. This medication should be considered as a therapeutic option for some patients with symptomatic male testosterone deficiency.

 

[Michael Scally MD]

Novarino G, El-Fishawy P, Kayserili H, et al. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy. Science. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy

Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1-? subunit of branched chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK mRNA and protein, E1-? phosphorylation, and plasma branched chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.

 

[Michael Scally MD]

Bhattacharya RK, Khera M, Blick G, Kushner H, Miner MM. Testosterone replacement therapy among elderly males: the Testim Registry in the US (TRiUS). Clin Interv Aging 2012;7:321-30. Testosterone replacement therapy among elderly males: the Testim Regis

BACKGROUND: Testosterone levels naturally decline with age in men, often resulting in testosterone deficiency (hypogonadism). However, few studies have examined hypogonadal characteristics and treatment in older (>/=65 years) men.

OBJECTIVE: To compare data at baseline and after 12 months of testosterone replacement therapy (TRT) in hypogonadal men >/=65 vs <65 years old. Data for participants 65-74 vs >/=75 years old were also compared. METHODS: Data were from TRiUS (Testim Registry in the United States), which enrolled 849 hypogonadal men treated with Testim((R)) 1% (50-100 mg testosterone gel/day) for the first time. Anthropometric, laboratory, and clinical measures were taken at baseline and 12 months, including primary outcomes of total testosterone (TT), free testosterone (FT), and prostate-specific antigen (PSA) levels. Comparisons of parameters were made using Fisher's exact test or analysis of variance. Nonparametric Spearman's rho and first-order partial correlation coefficients adjusted for the effect of age were used to examine bivariate correlations among parameters.

RESULTS: Of the registry participants at baseline with available age information, 16% (133/845) were >/=65 years old. They were similar to men <65 years old in the duration of hypogonad-ism prior to enrollment ( approximately 1 year), TT and FT levels at baseline, TT and FT levels at 12-month follow-up, and in reported compliance with treatment. Older patients were more likely to receive lower doses of TRT. PSA levels did not statistically differ between groups after 12 months of TRT (2.18 +/- 2.18 ng/mL for >/=65 vs 1.14 +/- 0.84 ng/mL for <65 years old, P = 0.1). Baseline values for the >75-year-old subcohort were not significantly different from subcohorts aged 65-74 years and <65 years.

CONCLUSION: Hypogonadal men >/=65 years old showed significant benefit from TRT over 12 months, similar to that found for hypogonadal men <65 years old. TRT was well tolerated in older patients, successfully increased testosterone level regardless of age, and did not significantly increase PSA levels in older men.

 

[Michael Scally MD]

Ziehn MO, Avedisian AA, Dervin SM, Umeda EA, O'Dell TJ, Voskuhl RR. Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in the Hippocampus during Autoimmune Demyelinating Disease. J Neurosci 2012;32(36):12312-24. Therapeutic Testosterone Administration Preserves Excitatory Synaptic Transmission in the Hippocampus during Autoimmune Demyelinating Disease

Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in >30% of these patients. While postmortem pathology studies and in vivo magnetic resonance imaging demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS.

The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (postdisease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal CA1, decreased presynaptic (Synapsin-1) and postsynaptic (postsynaptic density 95; PSD-95) staining, diffuse demyelination, and microglial activation.

Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as presynaptic and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in EPSPs are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE.

This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease.

 

[Michael Scally MD]

Aydogan U, Aydogdu A, Akbulut H, et al. Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Endocr J. https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ12-0134/_pdf

Hypogonadotropic hypogonadism is defined as the failure in production of gonadal hormones, thus resulting in lower amounts of testosterone. Depression, anxiety and decreased quality of life are the most common psychopathological conditions in young hypogonadal men. The aim of the present study was to assess the still debated relationship with testosterone levels and psychological symptoms in young male patients with congenital hypogonadotropic hypogonadism (CHH). 39 young male patients with CHH and 40 age-matched healthy males were enrolled in the present study. The impact of testosterone replacement treatment (TRT) on the patients' anxiety and depression levels, sexual function and quality of life were assessed before and after 6 months of treatment using valid and reliable scales, including the Short Form-36 (SF-36), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Arizona Sexual Experiences (ASEX). Patients with CHH had significantly higher scores for BDI, BAI, and ASEX than the control subjects at baseline (p=0.011, p=0.036, p<0.001, respectively). The ASEX and BDI scores significantly improved after the TRT (p<0.001 for both), while the improvement in the BAI score was not statistically significant (p=0.135). When compared to the control group, treatment naive hypogonadal patients had more severe symptoms of sexual dysfunction, anxiety, depression, and worse quality of life. After 6 months of TRT, we observed improvements in the above parameters, suggesting that low endogenous levels of testosterone might be related to the increased incidence of psychological symptoms.

 

[Michael Scally MD]

Veldhuis JD, Norman C, Miles JM, Bowers CY. Sex Steroids, GHRH, Somatostatin, IGF-I, and IGFBP-1 Modulate Ghrelin’s Dose-Dependent Drive of Pulsatile GH Secretion in Healthy Older Men. Journal of Clinical Endocrinology & Metabolism. Sex Steroids, GHRH, Somatostatin, IGF-I, and IGFBP-1 Modulate Ghrelin’s Dose-Dependent Drive of Pulsatile GH Secretion in Healthy Older Men

Context: Ghrelin is a potent endogenous stimulator of GH secretion. However, clinical factors that regulate ghrelin dose-responsiveness are incompletely defined.

Objective: The aim of the study was to test the multipathway hypothesis that testosterone (T) and estradiol, GHRH, and somatostatin (SS) jointly modulate ghrelin’s action.

Design/Participants/Setting: Healthy older men (n = 21) participated in a double-blind, prospectively randomized, placebo (Pl)-controlled study in a Clinical Translational Research Center.

Interventions: To create a range of sex-steroid milieus, men received leuprolide + Pl (n = 10) or leuprolide + T addback (n = 11). Sixteen to 21 d later, subjects received three separate randomly ordered overnight constant iv infusions of saline, GHRH, and SS. Interactions between the peptide clamp and ghrelin were tested by superimposed injections of four randomly ordered bolus iv doses of ghrelin (0.03, 0.135, 0.60, and 2.7 ?g/kg). GH was measured every 10 min, and GH responses were assessed by nonlinear dose-response analysis. Linear associations were assessed by stepwise regression.

Outcome Measures/Results: The descending numerical order of ghrelin efficacy (maximal GH secretory-burst mass; micrograms/liter) was 107 (GHRH + Pl), 104 (GHRH + T), 73 (saline + T), 73 (SS + T), 60 (saline + Pl), and 52 (SS + Pl) [means], wherein SS + T exceeded SS + Pl. GHRH and IGF binding protein-1 augmented, whereas IGF-I attenuated ghrelin potency. Age and IGF-I decreased ghrelin/GHRH synergy. Ghrelin sensitivity was independent of interventions.

Conclusions: These studies introduce composite regulatory effects of sex hormones, GHRH, SS, IGF binding protein-1, and IGF-I on ghrelin dose-responsiveness, suggesting multipathway modulation of GH-secretagogue action.

 

[Michael Scally MD]

Cattaneo A et al., Candidate Genes Expression Profile Associated with Antidepressants Response in the GENDEP Study: Differentiating between Baseline ‘Predictors’ and Longitudinal ‘Targets.’ Neuropsychopharmacology. Neuropsychopharmacology - Candidate Genes Expression Profile Associated with Antidepressants Response in the GENDEP Study: Differentiating between Baseline /`Predictors/' and Longitudinal /`Targets/'

To improve the ‘personalized-medicine’ approach to the treatment of depression, we need to identify biomarkers that, assessed before starting treatment, predict future response to antidepressants (‘predictors’), as well as biomarkers that are targeted by antidepressants and change longitudinally during the treatment (‘targets’).

In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1?, IL-1?, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-?), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n=34) and depressed patients (n=74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study.

Non-responders had higher baseline mRNA levels of IL-1? (+33%), MIF(+48%), and TNF-? (+39%). Antidepressants reduced the levels of IL-1?(?6%) and MIF (?24%), and increased the levels of GR (+5%) and p11 (+8%), but these changes were not associated with treatment response. In contrast, successful antidepressant response was associated with a reduction in the levels of IL-6 (?9%) and of FKBP5 (?11%), and with an increase in the levels of BDNF (+48%) and VGF (+20%)—that is, response was associated with changes in genes that did not predict, at the baseline, the response.

Our findings indicate a dissociation between ‘predictors’ and ‘targets’ of antidepressant responders. Indeed, while higher levels of proinflammatory cytokines predict lack of future response to antidepressants, changes in inflammation associated with antidepressant response are not reflected by all cytokines at the same time. In contrast, modulation of the GR complex and of neuroplasticity is needed to observe a therapeutic antidepressant effect.

 

[Michael Scally MD]

Twig G, Afek A, Shamiss A, et al. White Blood Cells Count and Incidence of Type 2 Diabetes in Young Men. Diabetes Care. White Blood Cells Count and Incidence of Type 2 Diabetes in Young Men

OBJECTIVE Association between white blood cell (WBC) count and diabetes risk has been recently suggested. We assessed whether WBC count is an independent risk factor for diabetes incidence among young healthy adults.

RESEARCH DESIGN AND METHODS WBC count was measured in 24,897 young (mean age 30.8 ± 5.36 years), normoglycemic men with WBC range of 3,000 to 12,000 cells/mm3. Participants were periodically screened for diabetes during a mean follow-up of 7.5 years.

RESULTS During 185,354 person-years of follow-up, diabetes was diagnosed in 447 subjects. A multivariate model adjusted for age, BMI, family history of diabetes, physical activity, and fasting glucose and triglyceride levels revealed a 7.6% increase in incident diabetes for every increment of 1,000 cells/mm3 (P = 0.046). When grouped in quintiles, a baseline WBC count above 6,900 cells/mm3 had an independent 52% increase in diabetes risk (hazard ratio 1.52 [95% CI 1.06–2.18]) compared with the lowest quintile (WBC <5,400 cells/mm3). Men at the lowest WBC quintile were protected from diabetes incidence even in the presence of overweight, family history of diabetes, or elevated triglyceride levels. After simultaneous control for risk factors, BMI was the primary contributor of the variation in multivariate models (P < 0.001), followed by age and WBC count (P < 0.001), and family history of diabetes and triglyceride levels (P = 0.12).

CONCLUSIONS WBC count, a commonly used and widely available test, is an independent risk factor for diabetes in young men at values well within the normal range.