OnLine First 2013

Smith RP, Khanna A, Coward RM, et al. Factors Influencing Patient Decisions to Initiate and Discontinue Subcutaneous Testosterone Pellets (Testopel) for Treatment of Hypogonadism. The Journal of Sexual Medicine. Factors Influencing Patient Decisions to Initiate and Discontinue Subcutaneous Testosterone Pellets (Testopel) for Treatment of Hypogonadism - Smith - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction - A variety of modalities for testosterone replacement therapy (TRT) are available, including topical gels, injections, and Testopel subcutaneous testosterone pellets (STP). STP are becoming more commonly utilized in the United States; however, patient preferences, expectations, and usage patterns regarding this therapy remain poorly characterized.

Aim - To identify factors influencing patients' decisions to initiate or discontinue STP.

Methods - A total of 175 men from an academic urology clinic who were currently using or who had previously used STP for hypogonadism received a 32-item electronic survey.

Main Outcome Measures - Assessment of the impact of convenience, efficacy, side effects, cost, and symptom relief on initiation and discontinuation of STP.

Results - One hundred and thirteen men (64.6% response rate) of mean age 51.4 years who previously underwent a mean of 2.8 STP implant procedures completed the survey. Fifty-nine (52.2%) and 40 (35.4%) men had switched to STP from topical gel and injection therapy, respectively, whereas 14 (12.4%) men initially started TRT with STP. Convenience (68.8%) was the most important factor in patients' decision to start STP, while cost of the previous form of TRT (14.7%) was least important. At the time of the survey, 32 men (28.3%) had discontinued STP therapy. Cost of therapy (50%) was the primary factor in discontinuing STP. There was no difference in serum testosterone levels between men who continued STP and those who discontinued therapy (642.8 vs. 629.0?ng/dL, P?=?0.83). Overall, 68.1% of patients continued STP therapy at the time of survey completion.

Conclusions - Convenience is the most important factor in a patient's decision to initiate STP; however, physician recommendation also plays a substantial role. Cost was the primary reason for discontinuation. Upon survey completion, greater than two-thirds of respondents elected to continue STP therapy. STP are a viable treatment option for hypogonadal men seeking a convenient and efficacious alternative modality of TRT.
 
IHighlights

• We apply a QSAR model and a Docking study in a heterogeneous data set of 269 AS.
• The QSAR model for the AS explains structural features of the steroidal backbone.
• Docking procedure predict the association of AS with the human androgen receptor.
• 14 steroids were identified as lead; the best was 7?-Methylestr-4-en-3,17-dione.


Alvarez-Ginarte YM, Montero-Cabrera LA, Garcia-de la Vega JM, et al. Integration of Ligand and Structure-Based Virtual Screening for Identification of Leading Anabolic Steroids. J Steroid Biochem Mol Biol. Integration of Ligand and Structure-Based Virtual Screening for Identification of Leading Anabolic Steroids

Parallel ligand- and structure-based virtual screenings of 269 steroids with anabolic activity evaluated in vivo were performed. The quantitative structure-activity relationship (QSAR) model expressed by selected descriptors as the octanol-water partition coefficient, the molar volume and the quantum mechanical calculated charge values on atoms C1, C2, C5, C9, C10, C14 and C17 of the steroid skeleton, expresses structural features of anabolic steroids (AS) contributing to the transport and steroid-receptor interaction.

On the other hand, computational simulations of a candidate ligand binding to a receptor study (a "docking" procedure) predict the association of these AS with the human androgen receptor (AR). Fourteen compounds were identified as lead; the most potent was the 7alpha-Methylestr-4-en-3, 17-dione.

It was concluded that a good anabolic activity requires hydrogen bonding interactions between both Arg752 and Gln711 residues in the cycles A with O3 atom of the steroid and either Asn705 and Thr877 residues in the cycles D of steroid with O17 atom.
 
[Rats] Reduction Of Testosterone Is Required For Testosterone's Inhibition Of The Hypothalamo-Pituitary-Adrenal Axis Response To Restraint Stress

Highlights
• Restraint stress- induced increases in plasma corticosterone are augmented after orchidectomy.
• Treatment of intact males with finasteride enhances restraint stress-induced corticosterone.
• Androgen treatment reduce the restraint stress-induced increase in plasma corticosterone
• Finasteride treatment blocks testosterone?s ability to reduce corticosterone.

Handa RJ, Kudwa AE, Donner NC, McGivern RF, Brown R. Central 5-Alpha Reduction Of Testosterone Is Required For Testosterone's Inhibition Of The Hypothalamo-Pituitary-Adrenal Axis Response To Restraint Stress In Adult Male Rats. Brain Res. Central 5-Alpha Reduction Of Testosterone Is Required For Testosterone?s Inhibition Of The Hypothalamo-Pituitary-Adrenal Axis Response To Restraint Stress In Adult Male Rats

In rodents, the hypothalamo-pituitary-adrenal (HPA) axis is controlled by a precise regulatory mechanism that is influenced by circulating gonadal and adrenal hormones. In males, gonadectomy increases the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) response to stressors, and androgen replacement returns the response to that of the intact male. Testosterone (T) actions in regulating HPA activity may be through aromatization to estradiol, or by 5alpha-reduction to the more potent androgen, dihydrotestosterone (DHT).

To determine if the latter pathway is involved, we assessed the function of the HPA axis response to restraint stress following hormone treatments, or after peripheral or central treatment with the 5alpha-reductase inhibitor, finasteride. Initially, we examined the timecourse whereby gonadectomy alters the CORT response to restraint stress. Enhanced CORT responses were evident within 48hrs following gonadectomy.

Correspondingly, treatment of intact male rats with the 5alpha-reductase inhibitor, finasteride, for 48h, enhanced the CORT and ACTH response to restraint stress. Peripheral injections of gonadectomized male rats with DHT or T for 48h reduced the ACTH and CORT response to restraint stress. The effects of T, but not DHT, could be blocked by the third ventricle administration of finasteride prior to stress application.

These data indicate that the actions of T in modulating HPA axis activity involve 5alpha-reductase within the central nervous system. These results further our understanding of how T acts to modulate the neuroendocrine stress responses and indicate that 5alpha reduction to DHT is a necessary step for T action.
 
[Rats] The Opposing Roles of Nitric Oxide and cGMP in the Age-Associated Decline Testicular Steroidogenesis -

Sokanovic SJ, Baburski AZ, Janjic MM, et al. The Opposing Roles of Nitric Oxide and cGMP in the Age-Associated Decline in Rat Testicular Steroidogenesis. Endocrinology. The Opposing Roles of Nitric Oxide and cGMP in the Age-Associated Decline in Rat Testicular Steroidogenesis

The molecular mechanism of the aging-associated dysfunction of Leydig cells (LCs) is complex and poorly understood. In this study, we analyzed the contribution of nitric oxide (NO) and cGMP signaling to the age-dependent decline in LC function.

Significant (>50%) decreases in serum, intratesticular, and LC androgens in aging rats (15-24 months) were accompanied by a proportional increase in NO production, an up-regulation of cGMP levels, and the expression of soluble guanylyl cyclase-1B and protein kinase G1 in LCs. In contrast, LC cAMP levels decreased with age, most likely reflecting the up-regulation of cAMP-specific phosphodiesterase expression. Moreover, the expression of genes encoding enzymes responsible for cholesterol transport and its conversion to testosterone were reduced.

Exposing LCs from aged animals to NO further increased cGMP levels and decreased cAMP and androgen production, whereas the addition of cell-permeable 8-Br-cGMP alone had the opposite effect. In vivo inhibition of cGMP-specific phosphodiesterase-5 for 3 and 6 months in aged rats led to a partial restoration of androgens, NO and cyclic nucleotide levels, as well as the expression of steroidogenic and NO/cGMP signaling genes.

These results indicate that a progressive increase in NO production contributes to the age-dependent decrease in steroidogenesis in a cGMP-independent manner, whereas the sustained elevation in cGMP levels significantly slows the decline in LC function.
 
Damar E, Toklu Y, Tuncel A, et al. Does Therapeutic Dose of Sildenafil Citrate Treatment Lead to Central Serous Chorioretinopathy in Patients With Erectile Dysfunction? American Journal of Men's Health 2013;7(5):439-43. Does Therapeutic Dose of Sildenafil Citrate Treatment Lead to Central Serous Chorioretinopathy in Patients With Erectile Dysfunction?

The possible effects of sildenafil citrate administration at therapeutic dosage on visual acuity, color vision, intraocular pressure, macular thickness, macular volume, and central serous chorioretinopathy in patients with erectile dysfunction were evaluated. The study consisted of 43 male patients diagnosed as having erectile dysfunction according to the first five question version of International Index of Erectile Function (IIEF-5). All patients were given sildenafil citrate 50 mg po 2 to 3 times/week for a month. The patients were evaluated at the first week and at the end of the treatment. The macular thickness and volume assessments with optic coherence tomography did not differ significantly in foveal, parafoveal areas, parafoveal superior hemisphere, parafoveal inferior hemisphere, parafoveal temporal, superior, nasal, and inferior quadrants. Central serous chorioretinopathy was not found in any of the patients.
 
García-Cruz E, Leibar-Tamayo A, Romero J, et al. Metabolic Syndrome in Men with Low Testosterone Levels: Relationship with Cardiovascular Risk Factors and Comorbidities and with Erectile Dysfunction. The Journal of Sexual Medicine. Metabolic Syndrome in Men with Low Testosterone Levels: Relationship with Cardiovascular Risk Factors and Comorbidities and with Erectile Dysfunction - Garc[]a-Cruz - 2013 - The Journal of Sexual Medicine - Wiley Online Library

Introduction Testosterone deficiency and metabolic syndrome (MetS) are strongly associated. Patients consulting for sexual dysfunction may have testosterone deficiency, providing a valuable opportunity to assess MetS. The identification of variables predicting MetS is of great importance.

Aims To identify cardiovascular comorbidities and risk factors, including erectile dysfunction (ED), associated with MetS in men aged ?45 with total testosterone (TT)?<?8?nmol/L (or <12?nmol/L when calculated free testosterone was?<250?pmol/L) and to gain further insight into the relationship between both conditions.

Methods Data were collected from a multicenter, cross-sectional, observational study conducted in Spain among men visiting men's health-care offices with a confirmed diagnosis of testosterone deficiency. Subjects with data for MetS assessment were included in this analysis. Other data available were anthropometrics, toxic habits, cardiovascular comorbidities, ED diagnosis, and TT values.

Main Outcome Measures The MetS harmonized definition was used. Waist circumference threshold was 94?cm. ED was diagnosed and classified using the International Index of Erectile Function-5 (IIEF-5) questionnaire. Bivariate and multivariate logistic regression analyses were performed to calculate odds ratios (ORs) for MetS.

Results Mean age was 61.2?±?8.1 years. Prevalences of ED and MetS were 97.6% and 69%, respectively, both increasing with age. Bivariate analysis showed that moderate or severe ED, obesity, and peripheral vascular disease (PVD) were the variables associated with the greatest odds of MetS (OR?=?2.672 and 2.514, respectively), followed by alcohol intake (OR?=?1.911). Tobacco use, ag,e and testosterone deficiency severity had a minimal effect that disappeared on multivariate analysis. Elevated triglycerides and HDL-cholesterol were MetS risk factors associated with a lower TT level.

Conclusion The high prevalence of MetS among men with testosterone deficiency highlights the opportunity to assess cardiovascular health in patients consulting for sexual dysfunction. Moderate to severe ED, obesity, PVD, and alcohol intake significantly increase the likelihood of MetS.
 
[LOW] Serum Testosterone Levels and [POOR] Clinical Outcomes in Male Hemodialysis Patients

Bello AK, Stenvinkel P, Lin M, et al. Serum Testosterone Levels and Clinical Outcomes in Male Hemodialysis Patients. Am J Kidney Dis. Serum Testosterone Levels and Clinical Outcomes in Male Hemodialysis Patients

BACKGROUND: Studies linking low serum testosterone concentration to adverse clinical outcomes in hemodialysis patients have been relatively small. We investigated the role of testosterone in adverse outcomes and quality of life in an incident cohort of male Canadian hemodialysis patients.

STUDY DESIGN: A prospectively designed multicenter observational study using data from the Canadian Kidney Disease Cohort Study (CKDCS).

SETTING & PARTICIPANTS: Male patients initiating hemodialysis therapy since February 14, 2005, in 3 Canadian centers serving ethnically diverse populations were studied (N = 623).

PREDICTOR: Serum testosterone levels using the International Society of Andrology, International Society for the Study of the Aging Male, and European Association of Urology cutoffs (low, <231 ng/dL; borderline, 231-346 ng/dL; normal, >346 ng/dL).

OUTCOMES: All-cause mortality, fatal and nonfatal cardiovascular (CV) events, and Health Utility Index (HUI)-assessed health-related quality of life.

MEASUREMENTS: Participants completed a structured interview on demographics and medical history and an HUI questionnaire (version 3). Routine laboratory test results captured into the study database, and serum testosterone measured within 3 months after initiation of the baseline hemodialysis session.

RESULTS: During a median follow-up of 20 (range, 1-81) months, 166 (27%) died and 98 (20%) had a CV event. Mean serum testosterone level was 234.1 +/- 146.1 (SD) ng/dL. Higher serum testosterone levels were associated with significantly decreased unadjusted risk of death (HR per 10-ng/dL increase, 0.58; 95% CI, 0.37-0.90). There was a statistically significant trend for higher all-cause mortality with low serum testosterone levels in adjusted analyses (P < 0.001). Higher levels of log-transformed testosterone were associated with significantly higher HUI scores (P for trend <0.001), and low levels of serum testosterone were associated significantly with lower HUI scores (P for trend <0.001). Although there was a significant trend in the unadjusted risk of CV events among participants with low serum testosterone levels (P < 0.001), the risk was no longer significant after adjustment for age. There was no significant interaction with age and serum testosterone level tested as continuous variables (P = 0.07).

LIMITATIONS: A short follow-up period and serum testosterone measured on a single occasion.

CONCLUSIONS: Low serum testosterone concentration may be a modifiable risk factor for adverse outcomes and poor quality of life in male hemodialysis patients. This hypothesis should be tested in randomized controlled trials.
 
Haring R, Baumeister SE, Nauck M, et al. Testosterone and cardiometabolic risk in the general population - the impact of measurement method on risk associations: a comparative study between immunoassay and mass spectrometry. European Journal of Endocrinology. Testosterone and cardiometabolic risk in the general population - the impact of measurement method on risk associations: a comparative study between immunoassay and mass spectrometry

Objective: Low total testosterone (TT) serum concentrations in men have been associated with various cardiometabolic risk factors. But given error-prone immunoassays used for TT assessment, upcoming mass spectrometry methods question the validity of these risk associations. Thus, we performed the first comparative study quantifying potential differences in the association of TT with cardiometabolic risk factors between the two methods.

Methods: We used data from 1,512 men aged 20-81 years, recruited for the cross-sectional population-based Study of Health in Pomerania (SHIP), Germany. TT was repeatedly measured by chemiluminescent immunoassay (CLIA, Immulite 2500) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We tested for significant differences between coefficients from CLIA- and LC-MS/MS-based multiple linear regression models associating TT with major cardiometabolic risk factors including adiposity, lipid metabolism, blood pressure, diabetic status, and inflammation.

Results: TT measurements by CLIA and LC-MS/MS yielded a Pearson correlation coefficient of 0.84. Only three of the ten tested associations for TT with cardiometabolic risk factor showed significant differences between the two measurement methods: in comparison to LC-MS/MS, CLIA-based TT assessment significantly underestimated risk associations of TT with waist circumference (ß: -0.54 vs. -0.63), body mass index (ß: -0.19 vs. -0.22), and ln-glucose levels (ß: -0.006 vs. -0.008).

Conclusion: In the present comparative study, the CLIA platform showed a reasonable measurement error and yielded comparable risk associations, providing little support to measure TT concentrations in men from the general population exclusively by LC-MS/MS.
 
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Caretta N, Feltrin G, Tarantini G, et al. Low Serum Testosterone as a New Risk Factor for Chronic Rejection in Heart Transplanted Men. Transplantation. Low Serum Testosterone as a New Risk Factor for Chronic Reje... : Transplantation

BACKGROUND: Among the various complications of heart transplantation (HTx), the vasculopathy of the allograft (CAV), a phenomenon of chronic rejection, is still a serious problem. Recently, the literature has shown that low testosterone levels in men are associated with cardiovascular disease. In this study, we evaluated the influence of testosterone plasma levels on CAV development.

METHODS: We studied, with a prospective observational study, all consecutive male HTx patients evaluated from May 2010 to June 2011 at our center. All subjects underwent accurate medical history collection, physical examination, biochemical blood tests, hormone levels, transthoracic Doppler echocardiography, coronary flow velocity reserve assessment, and coronary angiogram.

RESULTS: HTx subjects with CAV had significant lower total testosterone plasma levels (12.9+/-3.9 vs. 15.8+/-5.8 nmol/L), free testosterone (0.26+/-0.07 vs. 0.31+/-0.08 nmol/L), and coronary flow velocity reserve (2.35+/-0.60 vs. 2.81+/-0.78 s) with respect to No-CAV patients. Considering the patients as a whole group, a significant negative relation was found between free and total testosterone plasma levels and some cardiovascular risk factors (cholesterol and fasting blood glucose). A significant linear inverse relation was found between total and free testosterone plasma levels and CAV grading. Only free testosterone plasma levels were independent predictors for CAV.

CONCLUSIONS: We showed for the first time the influence of testosterone plasma levels on CAV development: indirectly increasing traditional risk factors and directly with a probable influence on alloimmune response.
 
Relationship between Erectile Dysfunction and Silent Coronary Artery Disease: Detection with Multidetector Computed Tomography Coronary Angiography

Umul M, Semerci B, Umul A, Ceylan N, Mammadov R, Turna B. Relationship between Erectile Dysfunction and Silent Coronary Artery Disease: Detection with Multidetector Computed Tomography Coronary Angiography. Urol Int. PayPerView: Relationship between Erectile Dysfunction and Silent Coronary Artery Disease: Detection with Multidetector Computed Tomography Coronary Angiography - Karger Publishers

Aim: Our aim was to determine the relationship between erectile dysfunction (ED) and silent coronary artery disease (CAD) by multidetector computed tomography (MDCT) coronary angiography.

Methods: Thirty consecutive men with nonhormonal and nonpsychogenic ED and with no cardiac symptoms were evaluated. Medical history, physical examination and laboratory investigation were performed. The five-item brief form of the International Index of Erectile Function (IIEF-5) was performed for evaluation of ED. The Agatston score (AS) was determined from MDCT images under beta blockade to induce bradycardia. The MDCT coronary angiography findings were evaluated by two radiologists blinded to the clinical findings. Patients were classified into three categories (mild, moderate and severe ED) according to IIEF-5 scores and into five categories (very low, low, moderate, moderately high and high CAD risk) according to the AS.

Results: Mean age was 58.3 +/- 8.7 years (46-79). 6 patients had hypertriglyceridemia, 4 had hypercholesterolemia and 4 had hyperglycemia. All patients had normal early morning testosterone levels. Regarding IIEF-5 scores, none of them had mild ED, 14 had moderate ED and 16 had severe ED. Of the 14 patients with moderate ED, 21.4% had low and 28.5% had moderate CAD risk regarding AS. Of the 16 patients with severe ED, 25% had moderate, 31.2% had moderately high and 25% had high CAD risk regarding AS. Increasing age was a risk factor for high AS (p = 0.045). There was a significant correlation between AS and ED severity (p = 0.01).

Conclusions: ED and CAD often coexist. MDCT coronary angiography can detect coronary lesions and allow appropriate medical intervention.
 
Kreitschmann-Andermahr I, Siegel S, Weber Carneiro R, Maubach JM, Harbeck B, Brabant G. Headache and pituitary disease A systematic review. Clinical Endocrinology. Headache and pituitary disease A systematic review - Kreitschmann-Andermahr - Clinical Endocrinology - Wiley Online Library

Headache is very common in pituitary disease and is reported to be present in more than a third of all patients with pituitary adenomas. Tumour size, cavernous sinus invasion, traction or displacement of intracranial pain-sensitive structures such as blood vessels, cranial nerves and dura mater, and hormonal hypersecretion are implicated causes.

The present review attempts to systematically review the literature for any combination of headache and pituitary or hormone overproduction or deficiency. Most data available are retrospective and/or not based on the International Headache Society (IHS) classification.

Whereas in pituitary apoplexy a mechanical component explains the almost universal association of the condition with headaches, this correlation is less clear in other forms of pituitary disease and a positive impact of surgery on headaches is not guaranteed. Similarly, invasion into the cavernous sinus or local inflammatory changes have been linked to headaches without convincing evidence. Some studies suggest that oversecretion of GH and prolactin may be important for the development of headaches and treatment, particularly with somatostatin analogues, has been shown to improve symptoms in these patients.

Otherwise, treatment rests on general treatment options for headaches based an accurate clinical history and a precise classification which includes assessment of the patient's psychosocial risk factors.
 
Atlantis E, Fahey P, Cochrane B, Wittert G, Smith S. Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis. BMJ Open 2013;3(8). Endogenous testosterone level and testosterone supplementation therapy in chronic obstructive pulmonary disease (COPD): a systematic review and meta-analysis -- Atlantis et al. 3 (8) -- BMJ Open

OBJECTIVE: Low testosterone level may be a reversible risk factor for functional disability and deterioration in patients with chronic obstructive pulmonary disease (COPD). We sought to systematically assess the endogenous testosterone levels and effect of testosterone therapy on exercise capacity and health-related quality of life (HRQoL) outcomes in COPD patients, as well as to inform guidelines and practice.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES: We searched PubMed, Scopus, Cochrane Library, CINAHL, Health Source Nursing and PsychINFO and the reference lists of retrieved articles published before May 2012.

INCLUSION CRITERIA: Observational studies on endogenous testosterone levels in people with chronic lung disease compared with controls, or randomised controlled trials (RCTs) on testosterone therapy for exercise capacity and/or HRQoL outcomes in COPD patients were eligible.

DATA EXTRACTION AND ANALYSIS: Data on the mean difference in endogenous total testosterone (TT) values, and the mean difference in exercise capacity and HRQoL values were extracted and pooled using random effects meta-analysis.

RESULTS: Nine observational studies in 2918 men with COPD reported consistently lower levels of TT compared with controls (weighted mean difference was -3.21 nmol/L (95% CI -5.18 to -1.23)). Six RCTs in 287 participants yielded five studies on peak muscle strength and peak cardiorespiratory fitness outcomes (peak oxygen uptake (VO2) and workload) and three studies on HRQoL outcomes. Testosterone therapies significantly improved peak muscle strength (standardised mean difference (SMD) was 0.31 (95% CI 0.05 to 0.56)) and peak workload (SMD was 0.27 (95% CI 0.01 to 0.52)) compared with control conditions (all but one used placebo), but not peak VO2 (SMD was 0.21 (95% CI -0.15 to 0.56)) or HRQoL (SMD was -0.03 (95% CI -0.32 to 0.25)).

CONCLUSIONS: Men with COPD have clinically relevant lower than normal TT levels. Insufficient evidence from short-term studies in predominately male COPD patients suggests that testosterone therapy improves exercise capacity outcomes, namely peak muscle strength and peak workload.
 
Gangopadhyay SS. Systemic administration of Follistatin288 increases muscle mass and reduces fat accumulation in mice. Sci Rep 2013;3:2441. Systemic administration of Follistatin288 increases muscle mass and reduces fat accumulation in mice : Scientific Reports : Nature Publishing Group

The present study describes the physiological response associated with daily subcutaneous injection of mice with recombinant follistatin288. This systemic administration of follistatin288 increases the follistatin levels in serum, indicating that the protein enters the circulation. The data suggest that a dose-dependent increase in body lean mass also occurs, together with an increase in muscle mass, possibly as a result of an increase in the size of the muscle fibers. After thirteen weeks of treatment, metabolic changes were observed; additionally, the switching of muscle fiber types was also apparent through myosin heavy chain remodeling, implying that changes are occurring at the molecular level. Furthermore, an increase in the muscle mass was associated with a significant decrease in the body fat mass. Overall, this study raises the possibility for the use of follistatin288 as an agent to treat muscle wasting diseases and/or to restrict fat accumulation by systemic administration of the protein.
 
Loves S, de Jong J, van Sorge A, et al. Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia. European Journal of Endocrinology. Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia

Introduction: Reduced testosterone levels are frequently observed in obese men. Increased aromatase activity may be an etiological factor.

Objective: To evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypotestosteronemia (OrHH).

Methods: Double-blind, placebo-controlled, 6-month trial in 42 obese men with a BMI > 35 kg/m2, and serum total testosterone levels < 10 nmol/L. All patients started on 1 tablet of 2.5 mg/week, with subsequent dose escalation every month until a serum total testosterone of 20 nmol/L was reached. Endpoints: psychological function, body composition, exercise capacity, and glucose, lipid and bone metabolism.

Results: 39 patients completed the study according to protocol. Letrozole decreased serum estradiol from 119.1 ± 10.1 to 59.2 ± 6.1 pmol/L (P < 0.001), increased serum LH from 3.3 ± 0.3 to 8.8 ± 0.9 U/L (P < 0.0001), and raised serum total testosterone from 8.6 ± 0.7 to 21.5 ± 1.3 nmol/L (P < 0.0001). Significant effects on the predefined endpoints were not observed.

Conclusion: Despite a marked rise in serum testosterone, low dose aromatase inhibition had no somatic or psychological effects in men with OrHH.
 
Maximum Inhibition Of Total Body Aromatization Obtained With Previously And Currently Used Aromatase Inhibitors

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Lonning PE, Eikesdal HP. Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved. Endocrine-Related Cancer 2013;20(4):R183-R201. Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved

Following their successful implementation for the treatment of metastatic breast cancer, the ‘third-generation’ aromatase inhibitors (anastrozole, letrozole, and exemestane) have now become standard adjuvant endocrine treatment for postmenopausal estrogen receptor-positive breast cancers.

These drugs are characterized by potent aromatase inhibition, causing >98% inhibition of estrogen synthesis in vivo. A recent meta-analysis found no difference in anti-tumor efficacy between these three compounds. As of today, aromatase inhibitor monotherapy and sequential treatment using tamoxifen followed by an aromatase inhibitor for a total of 5 years are considered equipotent treatment options.

However, current trials are addressing the potential benefit of extending treatment duration beyond 5 years. Regarding side effects, aromatase inhibitors are not found associated with enhanced risk of cardiovascular disease, and enhanced bone loss is prevented by adding bisphosphonates in concert for those at danger of developing osteoporosis. However, arthralgia and carpal tunnel syndrome preclude drug administration among a few patients.

While recent findings have questioned the use of aromatase inhibitors among overweight and, in particular, obese patients, this problem seems to focus on premenopausal patients treated with an aromatase inhibitor and an LH-RH analog in concert, questioning the efficacy of LH-RH analogs rather than aromatase inhibitors among overweight patients.

Finally, recent findings revealing a benefit from adding the mTOR inhibitor everolimus to endocrine treatment indicate targeted therapy against defined growth factor pathways to be a way forward, by reversing acquired resistance to endocrine therapy.
 

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[FAIL] d-Aspartic Acid Supplementation Has No Effect On Body Composition, Muscle Strength, And Serum Hormones

Willoughby DS, Leutholtz B. d-Aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men. Nutrition Research. d-Aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men

It was hypothesized that d-aspartic acid (D-ASP) supplementation would not increase endogenous testosterone levels or improve muscular performance associated with resistance training. Therefore, body composition, muscle strength, and serum hormone levels associated with the hypothalamo-pituitary-gonadal axis were studied after 28 days of resistance training and D-ASP supplementation.

Resistance-trained men resistance trained 4 times/wk for 28 days while orally ingesting either 3 g of placebo or 3 g of D-ASP. Data were analyzed with 2 × 2 analysis of variance (P < .05). Before and after resistance training and supplementation, body composition and muscle strength, serum gonadal hormones, and serum D-ASP and d-aspartate oxidase (DDO) were determined.

Body composition and muscle strength were significantly increased in both groups in response to resistance training (P < .05) but not different from one another (P > .05). Total and free testosterone, luteinizing hormone, gonadotropin-releasing hormone, and estradiol were unchanged with resistance training and D-ASP supplementation (P > .05). For serum D-ASP and DDO, D-ASP resulted in a slight increase compared with baseline levels (P > .05). For the D-ASP group, the levels of serum DDO were significantly increased compared with placebo (P < .05). The gonadal hormones were unaffected by 28 days of D-ASP supplementation and not associated with the observed increases in muscle strength and mass.

Therefore, at the dose provided, D-ASP supplementation is ineffective in up-regulating the activity of the hypothalamo-pituitary-gonadal axis and has no anabolic or ergogenic effects in skeletal muscle.
 
Chua ME, Escusa KG, Luna S, Tapia LC, Dofitas B, Morales M. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta-analysis. Andrology 2013;1(5):749-57. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta-analysis - Chua - 2013 - Andrology - Wiley Online Library

The aim of this study was to synthesize and present the latest available evidence regarding the use of oestrogen antagonists as empiric medical therapy for idiopathic male infertility with oligo and/or asthenoteratozoospermia through meta-analysis of randomized controlled trials (RCTs). Systematic literature acquisition was done for English and other foreign language biomedical databases up to March, 2013. RCTs relevant to the topic were identified and critically appraised independently by two physician reviewers.

Dichotomous data of pregnancy rate and adverse events were extracted for calculation of odds ratio (OR) and 95% confidence interval (CI). Effect estimates were pooled using Peto method with fixed effect model. The continuous data of semen and endocrine parameters were calculated for the mean difference between pre- and post-treatment effects, the weighted mean difference (WMD) and SD between the control and intervention group were determined and pooled using the random effects model. Inter-study heterogeneity and publication bias were assessed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline for meta-analysis reporting was followed. Eleven RCTs of good methodological quality were included for meta-analysis.

The pooled effect estimates showed that oestrogen antagonists use was associated with a statistically significant increased pregnancy rate compared with controls (pooled OR 2.42; 95% CI 1.47-3.94; p = 0.0004). Significant increase in sperm concentration (WMD 5.24; 95% CI 2.12, 88.37; p = 0.001) and per cent sperm motility (WMD 4.55; 95% CI 0.73, 8.37; p = 0.03) were also noted. While significant elevation of serum follicle stimulating hormone (WMD 4.19 95% CI 2.05, 6.34; p = 0.0001) and testosterone (WMD 54.59; 95% CI 15.92, 93.27; p = 0.006) was associated with its use.

No significant difference in adverse event was noted between oestrogen antagonists-treated group and controls. The evidence suggests that oestrogen antagonists as empiric medical therapy for idiopathic male infertility with low non-serious adverse event associated, may increase spontaneous pregnancy rate, improve sperm concentration and per cent sperm motility.
 
Ghalaut VS, Prakash G, Bansal P, et al. Effect of imatinib on male reproductive hormones in BCR-ABL positive CML patients: A preliminary report. J Oncol Pharm Pract. Effect of imatinib on male reproductive hormones in BCR-ABL positive CML patients: A preliminary report

Multiple animal studies, few clinical case reports and one study have observed decreased testosterone production and gynaecomastia as adverse effect of imatinib therapy. We have prospectively studied testosterone, LH and FSH levels at baseline and at 6 months of imatinib treatment in 34 newly diagnosed male BCR-ABL positive CML patients. While none of the patients had gynaecomastia at 6 months, the proportion of patients with low testosterone level increased significantly from 11.8% at baseline to 58.8% (p < 0.001) and those with high LH and FSH increased significantly from 26.4% and 23.5% to 82.4% and 76.4%, respectively (p < 0.001 and p < 0.001). Serum testosterone levels decreased significantly (p = 0.002) and serum LH and FSH levels increased significantly at 6 months of imatinib therapy (p = 0.001 and p = 0.003) in comparison to baseline levels. The findings document the effect of imatinib on testosterone levels in adult CML patients much before than reported earlier.
 
Poliwczak AR, Tylinska M, Broncel M. Effect of short-term testosterone replacement therapy on heart rate variability in men with hypoandrogen-metabolic syndrome. Pol Arch Med Wewn. Effect of short-term testosterone replacement therapy on heart rate variability in men with hypoandrogen-metabolic syndrome | POLSKIE ARCHIWUM MEDYCYNY WEWN?TRZNEJ

INTRODUCTION Testosterone deficiency syndrome (TDS) is characterized by clinical signs of testosterone deficiency accompanied by reduction in testosterone level. TDS leads to endothelial dysfunction which, apart from erectile dysfunction, accelerates progression of atherosclerosis.

OBJECTIVES Evaluation of testosterone supplementation in men with metabolic syndrome (MS) and TDS on autonomic balance assessed by heart rate variability (HRV) in 24-hour ECG Holter monitoring.

PATIENTS AND METHODS Eighty males divided into 3 groups - MS+TDS+(n = 30); MS+TDS-(n = 25) and healthy controls (n = 25) were included. Men (MS+TDS+) underwent 9 week intramuscular testosterone therapy (Omnadren 250). 24 hours ECG Holter monitoring was performed before start and at the end of the therapy.

RESULTS Almost all HRV parameters were significantly lower in men with MS+TDS+ compared to the control. Total power (TP), high (HF) and low frequency domain (LF) were significantly lower in MS+ TDS+ vs MS+TDS- groups. There were significant differences in SDNN (SD of NN intervals), SDNNI (SDNN index), SDANN (SD of the averages of 5-minute segments NN intervals) and ultra low frequency (ULF) domain between healthy subjects and MS+ TDS-. As a result of testosterone supplementation, a statistically significant increase was noted for SDNN, SDANN, TP, LF, VLF (very low frequency domain) and ULF. All, except for r-MSSD and TP, HF and LF/HF ratio values reached by these parameters still differ statistically from those in the healthy group.

CONCLUSIONS The 9-week-long testosterone supplementation therapy with beneficial effect on HRV could decrease the cardiovascular risk in men with MS and TDS.
 
Guo W, Li M, Bhasin S. Testosterone Supplementation Improves Anemia in Aging Male Mice. J Gerontol A Biol Sci Med Sci. Testosterone Supplementation Improves Anemia in Aging Male Mice

Whether aging alone causes anemia is still controversial. In this study, we show that 28-month-old male C57BL/6 mice, maintained in a pathogen-free environment, had significantly lower hemoglobin, hematocrit, and erythrocyte counts than young mice. The anemic condition aggravated further from 28 to 30 months. Old mice displayed increased erythropoietic activity, evidenced by an increase in reticulocyte counts, serum erythropoietin, and splenic expression of erythropoietic genes. An increase in late-stage erythroid progenitors was detected in spleen but not in bone marrow of the old mice. However, old mice also had lower serum iron and transferrin saturation, as well as lower erythrocyte iron incorporation rate. Testosterone supplementation restored serum iron status in old mice to levels similar to that of young adults, further upregulated splenic expression of erythropoietic genes, increased splenic erythroid progenitors, and significantly improved the red cell index. In conclusion, we found that mice can become anemic at very old age without apparent illness. The endogenous compensatory erythropoietic activity was insufficient to normalize the red cell index in old mice, either due to impaired iron homeostasis, ineffective erythropoiesis, or other unknown factors. Testosterone supplementation normalized the iron status and further stimulated splenic erythropoietic activity; both may contribute to improve the anemic condition in the old mice.
 
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