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Summary: Recently, it has been reported that treatment with testosterone (T) could have favorable effects on prostate inflammation; however, the data appear inconsistent. The main evidences concern experimental studies, and there is lower information obtainable from clinical studies. This study was conducted on patients with diagnosis of male accessory gland infection (MAGI) and a concomitant hormonal condition of acquired hypergonadotropic hypogonadism and has evaluated the effects on sperm parameters of the administration of a transdermal formulation of T gel for 3 months. The treated patients showed a significantly increased percentage of spermatozoa with normal form and progressive motility (p < .05 vs baseline), a significant reduction of CD45pos leucocytes in the semen (p < .05 vs baseline) and finally a significant increase of the seminal concentrations of zinc, fructose and alpha-glucosidase (p < .05 vs baseline) identified as key parameters associated to secretory function of the male accessory glands. The results of this study suggest the use of transdermal T in hypogonadal patients with MAGI for favorable effects on sperm parameters.

S. La Vignera, R. A. Condorelli, L. M. Mongioi, S. G. Vitale, G. I. Russo, A. S. Laganà, A. E. Calogero

First published: 24 November 2016
DOI: 10.1111/and.12745

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To determine the degree of transparency of health insurer policies regarding coverage of male sexual health conditions, we examined the publicly available policy coverage documents of the largest US medical insurance plans.

We selected two index patients across the male sexual health spectrum: (1) a PDE5 refractory erectile dysfunction patient requiring intracavernosal injection therapy or penile prosthesis, (2) a 50 yo male patient with laboratory-confirmed, symptomatic hypogonadism requiring testosterone replacement therapy as defined by endocrine society criteria. We researched the policy documents regarding coverage for standard therapies. We used breast reconstruction after mastectomy as a control.

We queried the publicly available policy statements for 84 of the largest health care plans in the United States. While breast reconstruction policies are publicly available for 94% of plans examined, policies of only 39% of plans for advanced ED treatment options and 62% for hypogonadism are publicly available. Of the plans that had publicly accessible data for erectile dysfunction coverage, 85% viewed penile prosthesis and intracavernosal injection as medically necessary, while 91% of viewed androgen replacement as medically necessary for our index patient.

There is a lack of transparency among medical insurers regarding coverage of ED and hypogonadism in stark contrast to reconstructive breast surgery.

Urology. 2016 Dec 23 [Epub ahead of print]

Brian V Le, Sarah McAchran, David Paolone, Daniel R Gralneck, Daniel Williams, Wade Bushman

Department of Urology, University of Wisconsin-Madison, Madison, WI. Electronic address: Leb@urology.wisc.edu., Department of Urology, University of Wisconsin-Madison, Madison, WI.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/28024968

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Abstract | CONTEXT: We hypothesize that endogenous sex steroids are associated with fracture risk independent of race/ethnicity.

DESIGN AND SETTING: We performed a nested case-control study within the prospective Women’s Health Initiative Observational Study (WHI-OS). Incident non-spine fractures were identified in 381 Black, 192 Hispanic, 112 Asian, and 46 Native American women over an average of 8.6 years. A random sample of 400 White women who experienced an incident fracture was chosen. One control was selected per case and matched on age, race/ethnicity, and blood draw date. Bioavailable estradiol (BioE2), testosterone (BioT) and sex hormone-binding globulin (SHBG) were measured using baseline fasting serum. Conditional logistic regression models calculated the odds ratio (OR) and 95% confidence interval (CI) of fracture across tertiles of hormone.

RESULTS: In multivariable and race/ethnicity adjusted models, higher BioE2 (>8.25 pg/ml) and higher BioT (>13.3 pg/ml) were associated with decreased risk of fracture, OR=0.65 (0.50-0.85), p trend=0.001 and OR=0.76 (0.60-0.96), p trend=0.02, respectively. The interaction term between race/ethnicity and either BioE2 or BioT was not significant. There was no association between SHBG and fracture risk. In models stratifying by race/ethnicity, higher BioE2 was associated with a lower risk of fracture in both White women, OR=0.56 (0.36-0.87) and Black women, OR=0.61 (0.39, 0.96). Higher BioT was associated with a significantly lower fracture risk in only Black women, OR=0.65 (0.43-0.97).

CONCLUSION: Serum BioE2 and BioT are associated with fracture risk in older women irrespective of race/ethnicity, independent of established risk factors for fracture.

Jane A. Cauley Michelle E. Danielson Guru Rajesh Jammy Doug C. Bauer Rebecca Jackson Jean Wactawski-Wende Rowan T. Chlebowski Kristine E. Ensrud Robert Boudreau

(2017) jc.2016-3589. DOI: https://doi.org/10.1210/jc.2016-3589

Published: 25 January 2017

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Abstract | Objective: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.

Design: Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women (n=32) and men (n=30), with normal weight and obesity (BMI>30 kg·m-2).

Methods: SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labelled hormones.

Results: Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI>40 kg·m-2) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels, was constant for testosterone, but not for estradiol. The impact of gender was maximal in morbid obesity, with men showing the highest binding / SHBG ratios.

Conclusions: The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender, and showing different structure, affinities for testosterone and estradiol, and also different immunoreactivity.

Maria del Mar Grasa, José Gulfo, Núria Camps, Rosa Alcalá, Laura Monserrat, José María Moreno-Navarrete, F Ortega, Montserrat Esteve, Xavier Remesar, José Antonio Fernández-López, José Manuel Fernández-Real and Marià Alemany⇑

– Author Affiliations

M Grasa, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Gulfo, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
N Camps, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
R Alcalá, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
L Monserrat, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Moreno-Navarrete, Endocrinology and Diabetes, Girona Institute of Biomedical Research and Hospital of Girona "Dr. Trueta", Girona, Spain
F Ortega, Endocrinology and Diabetes, Girona Institute of Biomedical Research and Hospital of Girona "Dr. Trueta", Girona, Spain
M Esteve, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
X Remesar, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Fernández-López, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Fernández-Real, Endocrinology and Diabetes, Girona Institute of Biomedical Research and Hospital of Girona "Dr. Trueta", Girona, Spain
M Alemany, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain

Correspondence: Marià Alemany, Email: malemany@ub.edu

Published online before print January 11, 2017, doi: 10.1530/EJE-16-0834
Eur J Endocrinol January 11, 2017 EJE-16-0834

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Summary | Background: Data on the effects of coenzyme Q10 (CoQ10) supplementation on metabolic profiles among subjects with polycystic ovary syndrome (PCOS) are scarce.

Objective: This study was carried out to evaluate the effects of CoQ10 supplementation on glucose metabolism and lipid profiles in subjects with PCOS.

Design, patients and measurements: This randomized, double-blind, placebo-controlled trial was conducted on 60 women diagnosed with PCOS. Subjects were randomly assigned into two groups to intake either 100 mg CoQ10 supplements (N = 30) or placebo (N = 30) per day for 12 weeks. Markers of insulin metabolism and lipid profiles were assessed at first and 12 weeks after the intervention.

Results: After 12 weeks of intervention, compared to the placebo, subjects who received CoQ10 supplements had significantly decreased fasting plasma glucose (−0·24 ± 0·51 vs +0·01 ± 0·44 mmol/l, P = 0·04), serum insulin concentrations (−7·8 ± 14·4 vs +6·0 ± 15·0 pmol/l, P < 0·001), the homeostasis model of assessment-estimated insulin resistance (−0·3 ± 0·6 vs +0·2 ± 0·6, P = 0·001), the homeostasis model of assessment-estimated B-cell function (−5·4 ± 9·5 vs +4·5 ± 9·9, P < 0·001) and increased the quantitative insulin sensitivity check index (+0·006 ± 0·009 vs −0·006 ± 0·01, P < 0·001). In addition, changes in serum total- (−0·10 ± 0·48 vs +0·19 ± 0·50 mmol/l, P = 0·02) and LDL-cholesterol concentrations (−0·15 ± 0·40 vs +0·14 ± 0·49 mmol/l, P = 0·01) in supplemented women were significantly different from those of women in the placebo group. When we adjusted the analysis for baseline values of biochemical parameters, age and baseline BMI, serum LDL-cholesterol (P = 0·05) became nonsignificant, and other findings did not alter.

Conclusions: Overall, CoQ10 supplementation for 12 weeks among subjects with PCOS had beneficial effects on glucose metabolism, serum total- and LDL-cholesterol levels.

Mansooreh Samimi, Maryam Zarezade Mehrizi, Fatemeh Foroozanfard, Hossein Akbari, Mehri Jamilian, Shahnaz Ahmadi, Zatollah Asemi

First published: 10 January 2017
DOI: 10.1111/cen.13288

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Abstract | Background: Reference ranges for testosterone are essential for making a diagnosis of hypogonadism in men.

Objective: To establish harmonized reference ranges for total testosterone in men that can be applied across laboratories by cross-calibrating cohort-specific assays to a reference method and standard.

Population: 9054 community-dwelling men in cohort studies in the United States and Europe: Framingham Heart Study; European Male Aging Study; Osteoporotic Fractures in Men Study; Male Sibling Study of Osteoporosis.

Methods: Testosterone concentrations in 100 participants in each of the four cohorts were measured using a reference method at Centers for Disease Control. Generalized additive models and Bland-Altman analyses supported the use of normalizing equations for transformation between cohort-specific and CDC values. Normalizing equations, generated using Passing-Bablok regression, were employed to generate harmonized values, which were used to derive standardized, age-specific reference ranges.

Results: Harmonization procedure reduced inter-cohort variation between testosterone measurements in men of similar ages. In healthy nonobese men, 19-39 years, harmonized 2.5th, 5th, 50th, 95th and 97.5th percentile values were 264, 303, 531, 852 and 916 ng/dL, respectively. Age-specific harmonized testosterone concentrations in nonobese men were similar across cohorts and greater than in all men.

Conclusion: The harmonized normal range (2.5th-to-97.5th percentile) in nonobese, population of European and American men, 19-39 years, is 264-916 ng/dL. A substantial proportion of inter-cohort variation in testosterone levels is due to assay differences. These data demonstrate the feasibility of generating harmonized reference ranges for testosterone that can be applied to assays, which have been calibrated to a reference method and calibrator.

Thomas G. Travison Hubert W. Vesper Eric Orwoll Frederick Wu Jean Marc Kaufman Ying Wang Bruno Lapauw Tom Fiers Alvin M. Matsumoto Shalender Bhasin

(2017) jc.2016-2935. DOI: https://doi.org/10.1210/jc.2016-2935
Published: 10 January 2017

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Abstract | Context: Endogenous testosterone levels have been negatively associated with QTc interval in small case series; the effects of testosterone therapy on electrocardiographic parameters have not been evaluated in randomized trials.

Objective: To evaluate the effects of testosterone replacement on corrected QT interval (QTcF) in two randomized controlled trials.

Participants: Men with pre- and post-randomization electrocardiograms (ECGs) from the Testosterone and Pain (TAP) and the Testosterone Effects on Atherosclerosis in Aging Men (TEAAM) Trials.

Interventions: Participants were randomized to either placebo or testosterone gel for 14 weeks (TAP) or 36 months (TEAAM). ECGs were performed at baseline and at the end of interventions in both trials; in the TEAAM trial ECGs were also obtained at 12 and 24 months.

Outcomes: Difference in change in the QTcF between testosterone and placebo groups was assessed in each trial. Association of changes in testosterone levels with changes in QTcF was analyzed in men assigned to the testosterone group of each trial.

Results: Mean total testosterone levels increased in the testosterone group of both trials. In the TAP trial, there was a non-significant reduction in mean QTcF in the testosterone group compared to placebo (effect size= -4.72 ms; p=0.228) and the changes in QTcF were negatively associated to changes in circulating testosterone (p=0.036). In the TEAAM trial, testosterone attenuated the age-related increase in QTcF seen in the placebo group (effect size= -6.30 ms; P<0.001).

Conclusion: Testosterone replacement attenuated the age-related increase in QTcF duration in men. The clinical implications of these findings require further investigation.

Affiliations
1Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
2Hacettepe University Faculty of Medicine, 06100 Ankara, Turkey;
3Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;
4Program on Aging, Hebrew Senior Life, Roslindale, MA;
5DWR Department of Geriatric Medicine, University of Oklahoma, Oklahoma City, OK;
6Kronos Longevity Research Institute, Phoenix, AZ;
7Phoenix VA Health Care System, Phoenix, AZ.

Thiago Gagliano-Jucá1,*, Tevhide Betül İçli2,*, Karol M. Pencina1, Zhuoying Li1, John Tapper3, Grace Huang1, Thomas G. Travison4, Panayiotis Tsitouras5,6, S. Mitchell Harman6,7, Thomas W. Storer1, Shalender Bhasin1, Shehzad Basaria1

Corresponding Author: Thiago Gagliano-Jucá, MD, PhD, Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115. Phone: +1 617-525-9150, Fax: +1 617-525-9148, Email: tgagliano@partners.org
*These authors contributed equally.
DOI: http://dx.doi.org/10.1210/jc.2016-3669
Received: November 09, 2016
Accepted: December 16, 2016
First Published Online: December 19, 2016

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Abstract | Context: Chronic psychological stress has been associated with shorter telomeres in some studies, but the underlying mechanisms are poorly understood. One possibility is that the neuroendocrine responses associated with stress exposure are involved.

Objective: To testing the hypothesis that greater cortisol responsivity to acute stressors predicts more rapid telomere attrition.

Design: We measured salivary cortisol responses to two challenging behavioral tasks. Leukocyte telomere length was measured at the time of mental stress testing and 3 years later.

Participants: We studied 411 initially healthy men and women aged 54-76 years.

Main outcome measure: Leukocyte telomere length.

Results: Cortisol responses to this protocol were small, we divided participants into cortisol responders (n = 156) and non-responders (n = 255) using a criterion (≥20%) previously shown to predict increases in cardiovascular disease risk. There was no significant association between cortisol responsivity and baseline telomere length, although cortisol responders tended to have somewhat shorter telomeres (β = -0.061, standard error 0.049). But cortisol responders had shorter telomeres and more rapid telomere attrition than non-responders on follow-up, after controlling statistically for age, gender, socioeconomic status, smoking, time of day of stress testing and baseline telomere length (β = -0.10, standard error 0.046, p = 0.029). The association was maintained after additional control for cardiovascular risk factors (β = -0.11, p = 0.031). The difference between cortisol responders and non-responders was equivalent to approximately 2 years in aging.

Conclusions: These findings suggest that cortisol responsivity may mediate in part the relationship between psychological stress and cellular aging.

Affiliations
1Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK
2School of Sport, Exercise, and Health Sciences, Loughborough University, Loughborough, UK
3Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
4Cardiff School of Health Sciences, Cardiff Metropolitan University, Cardiff, Wales, UK
– See more at: http://press.endocrine.org/doi/abs/10.1210/jc.2016-3035#sthash.ZmdnvuLr.dpufAndrew Steptoe1, Mark Hamer2, Jue Lin3, Elizabeth H. Blackburn3, and Jorge D. Erusalimsky4

Corresponding author: Dr Andrew Steptoe, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK. Tel: (44) 207 679 1804; email: a.steptoe@ucl.ac.uk

DOI: http://dx.doi.org/10.1210/jc.2016-3035
Received: August 21, 2016
Accepted: November 22, 2016
First Published Online: December 14, 2016

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Abstract | Introduction: Female sexual response is a complex phenomenon in which psychological, neurologic, and vascular mechanisms and hormonal factors interact. During the arousal phase, they cooperate to increase genital blood flow, thus inducing engorgement of the clitoris and lubrication of the vagina. Regulation of vascular and non-vascular smooth muscle tone is the crucial event in the erectile process. Preclinical studies have suggested that nitric oxide (NO) is the main vasodilator neurotransmitter modulating, through the second messenger cyclic guanosine monophosphate (cGMP), clitoral flow vessels.

Aim: To investigate the effects of sexual steroid hormones on pro-erectile and relaxant (mediated by NO and cGMP) and anti-erectile and contractile (mediated by ras homolog gene family member A [RhoA] and Rho-associated protein kinase [ROCK]) mechanisms in the clitoris using a validated animal model of female ovariectomized Sprague-Dawley rats.

Methods: Subgroups of ovariectomized rats were treated with 17β-estradiol, progesterone, testosterone, or testosterone and letrozole for 6 weeks. The experimental groups were compared with a control group of intact rats.

Main Outcome Measures: Sex steroids plasma levels were assessed and in vitro contractility studies were carried out in order to investigate the effect of ovariectomy and in vivo treatments on clitoris smooth muscle activity. Smooth muscle cells (SMCs) from rat clitoral biopsies were isolated and characterized. RhoA activity was determined in SMCs cell cultures. RNA from tissues and cells was analyzed by quantitative real-time RT-PCR.

Results: Using real-time polymerase chain reaction, testosterone treatment upregulated the expression of NO-mediated pathway genes (endothelial and neuronal NO synthase, guanylate cyclase soluble subunit-α3, guanylate cyclase soluble subunit-β3, cGMP-dependent protein kinase 1, and phosphodiesterase type 5). Conversely, estrogen replacement upregulated the expression of calcium-sensitizing RhoA-ROCK pathway genes. In vitro contractility studies were performed on phenylephrine pre-contracted clitoris strips. Ovariectomy resulted in a decreased responsiveness to Y-27632, a ROCK inhibitor, which was fully restored by 17β-estradiol supplementation. To further examine the effect of 17β-estradiol on the RhoA-ROCK pathway, smooth muscle cells were isolated from rat clitoris and their migration capacity was evaluated.

Conclusion: Collectively, these data demonstrate that testosterone improves the relaxation of vascular smooth muscle cells through the NO-cGMP pathway, and that testosterone and 17β-estradiol are necessary to maintain a functional contractile and relaxant machinery in the clitoris. This new concept might provide support for the concomitant use of estrogen and testosterone during the treatment of sexual arousal disorders related to hormonal imbalance or insufficiency.

Paolo Comeglio, PhD, Ilaria Cellai, PhD, Sandra Filippi, PhD, Chiara Corno, BSc, Francesca Corcetto, BSc, Annamaria Morelli, PhD, Elena Maneschi, PhD, Elisa Maseroli, MD, Edoardo Mannucci, MD, Massimiliano Fambrini, MD, Mario Maggi, MD, Linda Vignozzi, MD, PhDcorrespondencePress enter key for correspondence informationemailPress enter key to Email the author

DOI: http://dx.doi.org/10.1016/j.jsxm.2016.10.007

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Chronic opioid therapy for pain management is known to induce several endocrine changes. The authors examined the effect of testosterone supplemental therapy (TST) in patients with chronic, noncancer pain undergoing opioid therapy. It was hypothesized that treatment of opioid-induced hypogonadism (OIH) can reduce opioid requirements in patients suffering from chronic pain and approve their quality of life.

Over 18 months period, patients with OIH were identified in a tertiary referral pain center, Numerical Rating Scale (NRS) pain scores and daily morphine equivalent dose (MED) were the primary outcomes measured. Data were collected and comparative analysis performed between men undergoing TST versus nontreatment group. Twenty-seven OIH patients (total testosterone <300 ng/dL) were identified during the study period. TST group consists of 11 patients, while non-TST group consists of 16 patients as control cohort. Mean patient age (55 and 54.4, p = .4) and basic metabolic index (28.5 and 31.9, p = .07) in TST and non-TST groups, respectively. Mean follow-up total testosterone (ng/dL) was significantly higher after TST compared with the non-TST group (497.5 vs. 242.4 ng/dL, p = .03). Median follow-up NRS was 0 and 2 in the TST and non-TST groups (p = .02). Mean MED (mg) decreased by 21 mg in TST group and increased by 2.5 mg in non-TST group (p < .05). This study reports that treatment of OIH with TST can reduce opioid requirements in men with chronic pain as quantified by MED. It also confirms previous reports on the potential effects of OIH and that TST is effective in correcting opioid-induced endocrine abnormalities. Am J Mens Health October 7, 2016 Omer A. Raheem, MD¹, Sunil H. Patel, MD¹, David Sisul, MD¹, Tim J. Furnish, MD², Tung-Chin Hsieh, MD¹ ¹Department of Urology, University of California San Diego Health, San Diego, CA, USA ²Center for Pain Medicine, University of California San Diego Health system, San Diego, CA, USA Tung-Chin Hsieh, Department of Urology, University of California San Diego Health, 200 West Arbor Drive #8897, San Diego, CA 92103-8897