Sleep disturbance as a clinical sign for severe hypogonadism: efficacy of testosterone replacement therapy on sleep disturbance among hypogonadal men without obstructive sleep apnea

Objective: The present subanalysis of the EARTH study investigates the effects of one year testosterone replacement therapy (TRT) on sleep disturbance among hypogonadal men without obstructive sleep apnea.

Methods: Sleep disturbance was defined as three or more points in question 4 of the aging males symptoms (AMS) questionnaire. All participants completed the AMS scale, International Prostatic Symptoms Score (IPSS), Sexual Health Inventory for Men (SHIM) and Short Form 36 (SF-36) health survey at baseline and after 12?months. Sexual symptoms were also evaluated based on three AMS subscores (Q15, 16 and 17).

Results: We identified 100 patients with sleep disturbance, of whom 48 (24 each in the TRT and control groups) were ultimately included for analysis. All SF-36 categories , AMS scale, IPSS and SHIM score subdomains were significantly worse in patients with sleep disturbance than in those without disturbance. Statistically significant differences in sleep disturbance, erectile symptoms, sexual desire and some domains of the SF-36 were observed between the TRT and control groups after 12?months.

Conclusion: Sleep disturbance may be one of the clinical signs for severe hypogonadism. Moreover, TRT improved sleep conditions, sexual function and quality of life among hypogonadal men with sleep disturbance.     

Effects of testosterone replacement therapy on hypogonadal men with osteopenia or osteoporosis: a subanalysis of a prospective randomized controlled study in Japan (EARTH study)

Objective: We investigated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) among hypogonadal men with osteopenia/osteoporosis.

Methods: From our previous EARTH study population, 74 patients with a clinical diagnosis of osteopenia or osteoporosis and hypogonadism were included in this study, as the TRT (n?=?35) and control (n?=?34) groups. The TRT group was administered 250?mg of testosterone enanthate injection every 4 weeks for 12 months. The BMD, waist circumference, body mass index, body fat percentage, and muscle volume were measured at baseline and at 12 months. Blood biochemical data, including total cholesterol, triglycerides, HDL-cholesterol, hemoglobin A1c, and adiponectin values were also evaluated.

Results: At the 12-month visit, BMD significantly increased in both groups. However, comparisons on changes of parameter values from baseline to the 12-month visit between the TRT and control groups were significantly different in BMD (5.0?±?5.0 vs. 3.0?±?3.2; p?=?.0434) and in adiponectin value (?0.90?±?3.33 vs. 0.10?±?2.04; p?=?.0192). There were no significant changes in other parameters.

Conclusions: TRT for 12 months could improve BMD with a decrease in adiponectin levels among hypogonadal men with osteopenia/osteoporosis.     

Caffeine intake is not associated with serum testosterone levels in adult men: cross-sectional findings from the NHANES 1999–2004 and 2011–2012

Objective: The association of caffeine intake with testosterone remains unclear. We evaluated the association of caffeine intake with serum testosterone among American men and determined whether this association varied by race/ethnicity and measurements of adiposity.

Methods: Data were analyzed for 2581 men (≥20?years old) who participated in the cycles of the NHANES 1999–2004 and 2011–2012, a cross-sectional study. Testosterone (ng/mL) was measured by immunoassay among men who participated in the morning examination session. We analyzed 24-h dietary recall data to estimate caffeine intake (mg/day). Multivariable weighted linear regression models were conducted.

Results: We identified no linear relationship between caffeine intake and testosterone levels in the total population, but there was a non-linear association (p_nonlinearity?p_nonlinearity?≤?.03 both) and only among men with waist circumference <102?cm and body mass index <25?kg/m² (p_nonlinearity?Conclusion: No linear association was identified between levels of caffeine intake and testosterone in US men, but we observed a non-linear association, including among racial/ethnic groups and measurements of adiposity in this cross-sectional study. These associations are warranted to be investigated in larger prospective studies.     

Aging male symptomatology and eating behavior

Objective: The literature on eating disorders in older males is still very limited. We assessed the relationship between aging male symptomatology and eating behavior in middle-aged and older men.

Method: We distributed anonymous questionnaires to men aged 40–75?years living in or near Innsbruck, Austria, covering demographic items, current eating disorder symptoms (as defined by DSM-5), and associated measures of eating pathology, body image, and sports activity (including exercise addiction). We also administered the Aging Males’ Symptoms scale (AMS), and classified respondents as “high-AMS” (AMS score ≥37; N?=?82) or “low-AMS” (AMS score <37; N?=?386).

Results: High-AMS men reported a significantly higher mean current BMI, a greater prevalence of eating disorder symptoms, higher scores on the Eating Disorder Examination Questionnaire, greater risk of exercise addiction, and more negative body image than low-AMS men.

Discussion: We found a marked association between aging-male symptomatology and eating-disorder symptomatology in aging men. Our findings suggest that clinicians should carefully inquire about eating disorder symptoms in men aged 40 and above reporting aging-male symptomatology. Importantly, several men in the study reported “purging” via excessive exercise (as opposed to the more common methods of vomiting or use of laxatives or diuretics), and therefore this should be a subject of inquiry in clinical evaluations. To pursue these findings, subsequent studies of eating disorders in older men should consider assessing endocrinological measures, particularly testosterone levels, and should use longitudinal designs.     

Serum testosterone measurement in men: Evaluation of modern immunoassay technologies

Accurate measurement of serum testosterone (T) is essential for proper diagnosis of androgen deficiency. There are now several modern assay technologies, including automated ones, for measurement of T. In this study, we compared analytical performance of five modern immunoassay technologies commonly used for measurement of total T: Vitros ECi (Ortho-Clinical Diagnostics; normal range (n.r.) 4.6–34 nmol/L); Architect (Abbott Laboratories; n.r. 9.7–34 nmol/L); Access (Beckman Coulter; n.r. 5.3–23 nmol/L); Delfia (Perkin-Elmer; n.r. 9.3–34 nmol/L); and manual EIA DRG kits (n.r. 8.3–42 nmol/L), with the classical RIA (³H–T), after extraction (n.r. 11–33 nmol/L), as a reference method. Total T was measured using all above-mentioned methods in serum samples from 100 male patients, aged 16–65 years. Mean T concentrations in these 100 serum samples assayed by all non-isotopic methods were statistically significantly higher than those obtained by RIA. Delfia showed the highest T levels (19.3 nmol/L versus 12.1 nmol/L by RIA) with a positive bias 60–100%. Almost similar results were obtained using Architect, with a positive bias 40–70%. The closest correlation in results was found between Vitros ECi and RIA (12.7 nmol/L versus 12.1 nmol/L). In the studied samples, the median of differences ranged from minimal (?0.4 nmol/L for Vitros ECi) to maximal (?7.25 nmol/L for Delfia). For all non-isotopic methods, with the exception of Vitros ECi, differences in subjects with low T level (<10 nmol/L) were statistically significantly larger than in the subjects with high T (T > 10 nmol/L). All other methods showed different degrees of dissimilarities with the RIA, especially in the range of low testosterone concentrations, which is of importance in the clinical assessment of women and pubertal boys.     

Decline of serum levels of free testosterone in aging healthy Chinese men

Objective.?To investigate the age-related change of serum androgen levels in healthy men and to define a cut-off value of serum testosterone for the diagnosis of androgen deficiency in the aging male.

Method.?1080 healthy men aged 20 to ?70 years old were enrolled in Beijing, Shanghai, Xian and Chongqing. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), calculated free testosterone (cFT), sex hormone binding globulin (SHBG), 17beta-oestradiol (E2), the T/LH ratio, and T/SHBG as a free testosterone index (FTI) were all determined.

Results.?Serum total T did not significantly decline, but the cFT, T/LH and FTI progressively decreased with aging. To determine androgen deficiency, the 10th percentile value of men <40 years was defined as the lower cut-off value for cFT, T/LH or FTI, which were 0.3 nmol/L, 2.8 nmol/IU, and 0.4 nmol/IU respectively. With the median value of cFT of men aged between 20 and 49 years as the criterion, the level of cFT was lower in 2.82% of men from 40 to 49 years, in 19.53% from 50 to 59 years, in 22.57% from 60 to 69 years, and in 33.19% of men ?70 years. Taking the above value of cFT as the cut-off point, the prevalence of androgen deficiency in men 40–49 years was 13.0%, 31.8% in men 50–59 years, 30.1% in men 60 to 69 years, and 46.7% in men >70 years.

Conclusions.?(i). While serum total T values do not decline with aging, the levels of cFT gradually decline with aging; (ii) when using the value of cFT of the 10th percentile of men aged 20 to 39 years as the cut-off point, the prevalence of androgen deficiency was <15% before the age of 50 years, and about 30% thereafter, approaching 45% after the age of 70 years; and (iii) in this study the values of T/LH paralleled those of cFT closely; therefore, T/LH could serve as a surrogate for cFT.     

Time for international action on treating testosterone deficiency syndrome

Aim. Testosterone deficiency is having an increasing impact on men's health because of global aging, higher levels of obesity, diabetes and metabolic syndrome and adverse environmental factors such as stress xenoestrogens and anti-androgens. The question addressed is to what extent the large body of evidence on the benefits and safety of testosterone therapy is applied in clinical practice.

Methods. Demographic data for men over the age of 50 from different regions of the world have been compared with the number of men in that age group estimated from sales figures to be receiving testosterone treatment.

Results. On the basis of estimate that 20% of men over 50 in the general population of each region could be expected to have testosterone deficiency symptoms, on average only these men (0.69%) in most European countries were receiving treatment. Proportion was higher in the UK (1.00%) and Germany (1.89%), but lower in France (0.49%), Italy (0.51%) and Russia (0.54%). Interestingly, Australia had higher figures (1.64%), in spite of tight state control measures on androgen use. The USA has the highest treatment rate (7.96%) and this is increasing rapidly.

If the basis for the diagnosis was the more conventional combination of symptoms plus biochemical evidence of low total and free testosterone levels, androgen deficiency would be expected in at least 5% of men over 50, and percentage treatment rates therefore four times higher. However, even on that basis, only in the USA do these exceed 10%.

Conclusions. International action is urgently needed to raise awareness in the medical profession in the various countries of these remarkably low levels of testosterone treatment. Improvement in this requires education and motivation of doctors and those regulating the healthcare systems. A public awareness campaign is needed to educate men about the symptoms of testosterone deficiency and its impact on their health.     

Endogenous hydrogen sulfide insufficiency as a predictor of sexual dysfunction in aging rats

Objective: Our earlier studies showed that endogenous hydrogen sulfide (H₂S) pathway contributed significantly to erectile function. In this study, we tested the hypothesis that age-dependent changes in the bioavailability of H₂S increased the risk of erectile dysfunction (ED). Methods: Young, adult (3-month) and older (18-month) male Sprague-Dawley rats (n?=?6?8/group) were treated daily with sodium hydrosulfide hydrate (NaHS), DL-propargylglycine, sildenafil or l-NAME for 10 weeks. Subsequent to cavernous nerve electrical stimulation, intracavernosal pressure (ICP) responses were determined, and the samples were collected and processed for hormonal (plasma) and gaseous parameters (plasma and erectile corpus cavernosum [CC]) using standard assay protocols. Results: Aging significantly reduced the ICP response (35.9?±?2.0 mmHg vs. 45.2?±?1.9 mmHg in young controls), which was countered by NaHS (53.5?±?6.0) or sildenafil (52.8?±?9.8) treatment. In these rats, marked increments to testosterone (T) or estradiol resulted from NaHS supplementation. Similar to age-dependent decline in NO, the plasma and CC level of H₂S was significantly lower in senescent rats when compared with young animals (p?<?0.05). Conclusion: Our results confirm that ED with aging may be linked to a derangement in the H₂S pathway accompanied by low T levels. It is likely that a pharmacologic intervention delivering H₂S will provide additional benefits to sexual function from an improved T milieu.     

Testosterone deficiency in male heart failure patients and its effect on endothelial progenitor cells

Background: Endothelial progenitor cells (EPCs) are thought to contribute to reendothelialization and neoangiogenesis. Since it is known that EPCs express a testosterone receptor, we wanted to assess the prevalence of testosterone deficiency in patients with CHF and its impact on circulating EPCs. Methods: 137 male patients with chronic heart failure (CHF) were included (age 61?±?13 years; BMI 29?±?5?kg/m²; New York Heart Association classification (NYHA) I: n = 47, NYHA II: n = 51, NYHA III: n = 39). Numbers of different populations of circulating EPCs were quantified using flow cytometry. Levels of free testosterone and EPC-regulating cytokines were determined using ELISA. Results: The prevalence of testosterone deficiency in our University CHF clinic was 39%. However, there was no difference between patients with and without testosterone deficiency regarding their levels of EPCs. Testosterone levels were inversely correlated with age (R² = ?0.32, p = 0.001) and NYHA status (R² = 0.28, p = 0.001) and correlated with cardiorespiratory capacity (R² = 0.26, p = 0.03). Conclusion: Testosterone deficiency is frequent in male patients with CHF but does not appear to impact the regenerative EPCs.     

Effects of testosterone supplementation on prevention of age-related penile remodeling

Abstract

Erectile dysfunction develops among 46.2% of men between 40 and 70 years. Studies demonstrated substitution on detrusor muscle by collagen due testosterone deprivation. It is clear the correlation among aging and oxidative stress, accelerating apoptosis process in many tissues. This study aims to demonstrate the collagen substitution over the muscle fibers on muscle structure of rat’s penis and the effects of testosterone supplementation. Sixteen senescent Wistar rats were divided into two groups: treatment (receiving standard supplementation testosterone dose) and control (receiving equivalent saline solution). Testosterone was dosed on D0 and D56 of study. All penises were prepared with picrosirius colored histology; stereology was applied to determine the volumetric density of collagen fibers (Vv). Analysis of variance demonstrated testosterone group’s replacement therapy to be effective, while the androgenic decline continued by the time of experiment in control group (p?<?0.05). Testosterone group had Vv of 20.6%, lower than control group (47.8%); t-test (p?<?0.001). Pearson’s correlation demonstrated an inverse correlation between the Vv and testosterone’s levels (p?<?0.001). This is a pioneer study on demonstration of structural alterations over the cavernous corpora muscle caused by deprivation of testosterone on elderly rat. These finding implicate that the testosterone levels can influence, not only the libido, but also the erectile function.