Aging androgens and the metabolic syndrome

Objective: To assess the responses of a symptom complex related to partial androgen deficiency in the aging male (PADAM) to androgen supplementation. Subjects and methods: Eighty-six men from five hospitals in Beijing aged 50-70 years with symptoms related to PADAM received oral testosterone undecanoate for 2 months, and the effects of the therapy were evaluated. Results: After treatment, the symptom scores were significantly improved (all p < 0.001). Serum levels of luteinizing hormone and follicle stimulating hormone were suppressed, and free testosterone and albuminbound testosterone levels were elevated. However, they were not significantly different from the pretreatment values. Waist/hip ratio and blood pressure were markedly decreased, but no changes were found in serum levels of total cholesterol, triglyceride, albumin and prostate specific antigen. Conclusions: Two months of treatment with oral testosterone undecanoate clearly improved the symptoms related to PADAM. No statistical relationship was found between symptom improvement and androgen levels. Androgen therapy for 2 months was beneficial to the waist/hip ratio and blood pressure, and no harm was done to the prostate gland or lipid metabolism.     

Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone

Aims: To evaluate the cause of failure of sildenafil citrate (Viagra^®) to restore erections in patients with organic erectile dysfunction (ED) associated with type II diabetes mellitus (DM) and receiving oral antidiabetic drugs. Methods: Diabetic ED patients (n = 120), aged 43-74 years, failing to respond at least three times to 100 mg Viagra were evaluated. After at least 2 weeks' treatment with oral testosterone undecanoate (Andriol^®), 100 mg Viagra was used before coitus. ED was assessed with the International Index of Erectile Function (IIEF). Serum total testosterone, prolactin, thyroid stimulating hormone, lipid profile and prostate-specific antigen (PSA) were determined by standard methods and prostate volume by digital rectal examination. Age-matched diabetic ED patients (n = 100) served as controls for baseline values. Results: Viagra non-responders had, at baseline, significantly lower testosterone and more depressed libido than controls. Andriol restored testosterone to normal levels and increased libido. In 84/120 (70%) Viagra non-responders, combined therapy with Andriol induced satisfactory erections, a significant increase in IIEF scale (question (Q) 3 from 2.0 ± 0.2 to 3.7 ± 0.3, Q4 from 1.9 ± 0.1 to 3.4 ± 0.2, Q12 from 1.0 ± 0.1 to 4.2 ± 0.4) and increased sexual contacts from 0.5 to 3-4 per month. No adverse events were noted, and PSA levels remained below 4 ng/ml. Conclusion: Decreased testosterone levels in patients with ED and type II DM receiving oral antidiabetic agents may be responsible for failure to respond to sildenafil citrate therapy. Combination with oral testosterone undecanoate restores sexual function in these patients.     

The impact of testosterone replacement therapy on glycemic control,vascular function,and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes

Objective: This study set out to assess effects of testosterone replacement therapy (TRT) on parameters of metabolic syndrome and vascular function in obese hypogonadal males with type 2 diabetes mellitus (DM2).

Study design: Fifty-five obese hypogonadal diabetic males on oral hypoglycemic treatment were enrolled into this one-year, double-blind, randomized, placebo-controlled clinical study. Group T (n?=?28) was treated with testosterone undecanoate (1000?mg i.m. every 10?weeks) while group P (n?=?27) received placebo.

Methods: Anthropometrical and vascular measurements – flow-mediated dilatation (FMD) and intima media thickness (IMT) – biochemical and hormonal blood sample analyses were performed at the start of the study and after one year. Derived parameters (BMI, HOMA-IR, calculated free testosterone (cFT) and bioavailable testosterone (BT)) were calculated.

Results: TRT resulted in reduction of HOMA-IR by 4.64?±?4.25 (p?p?p?=?.005).

Conclusion: TRT normalized serum testosterone levels, improved glycemic control and endothelial function while exerting no ill effects on the study population.     

Association of DHEA-S and estradiol serum levels to symptoms of aging men

Objectives A number of interactions between agerelated changes in serum levels of dehydroepiandrostendione sulfate (DHEA-S) and estradiol and symptoms of aging men have been proposed, yet data regarding this issue are scant. We therefore set up a prospective study to analyze these associations. Methods In a prospective, cross-sectional study, men aged 45-85 years were recruited. All men completed a questionnaire containing 38 items covering a number of aspects of the aging male. Questionnaires were compiled by using items from previously published and validated questionnaires. Several socioeconomic parameters were also determined. In parallel, serum levels of testosterone, free testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), DHEA-S, estradiol, sex hormone binding globulin and prostate-specific antigen (PSA) were quantified by commercially available immunoassays. Results A total of 375 men with a mean age of 59.9 ± 9.2 years (mean ± standard deviation) were analyzed. Average DHEA-S and estradiol levels of 135.8 ± 90.9 μg/dl and 29.7 ± 14.6 pg/ml, respectively, were recorded. DHEA-S serum levels were negatively correlated to patient age, sexual function score, total score and PSA. Estradiol serum levels were positively correlated to testosterone and free testosterone. None of the other scores or questions revealed a correlation with DHEA-S or estradiol serum levels. Conclusion This prospective study elucidates only small interactions between partial androgen deficiency of the aging male (PADAM)-related symptoms and serum levels of DHEA-S and estradiol. Nevertheless, the data suggest an impact of DHEA-S on sexual function.     

Interleukin-18 and testosterone levels in men with metabolic syndrome

Objective: Interleukin 18 (IL-18) is an adipokine associated with obesity. Data about the relationship of IL-18 to the metabolic syndrome (MS) are still scarce. Low testosterone (T) levels are common in men with MS, but we did not find data about the levels of IL-18 in men with low T. The aim of this study was to determine the levels of IL-18 in men with MS with or without low T.

Patients and methods: A total of 251 men were included in the study. Of them 218 had MS (IDF 2005) and they were divided according to their morning total testosterone (TT) level (cutoff 10.4?nmol/l) into two groups: MS-low T (N?=?84) and MS-normal T (N?=?134). The control group consisted of 33 men without MS and low T. IL-18 was determined in serum using enzyme-linked immunosorbent assay. A small group of eight men with MS and low T levels received testosterone therapy for three months and physical and laboratory parameters were monitored at the end of that period.

Results: MS men were at mean age (±SD)?=?53.77?±?9.59 years; body mass index (BMI)?=?34.0?±?6.3?kg/m²; and TT?=?12.59?±?5.66?nmol/l. The control group was at age?=?52.12?±?5.2 years (NS); BMI?=?25.6?±?2.4?kg/m² (p?p?p?p?p?p?Conclusions: In this study, higher IL-18 levels were found in the presence of MS compared to healthy men, but they did not differ between men having MS with or without LOH.     

The imbalance of sex-hormones related to depressive symptoms in obese men

Obese men may present hypogonadothrofic hypogonadism, mainly related to higher insulinemia and aromatase activity. Our objectives were to evaluate the relationship of sex-hormones profiles and frequency of depressive symptoms in 43 obese men, in a cross-sectional study. They had 19–60 years, and body mass index 30–50?kg/m². LH, total and free testosterone (TT and FT), estradiol (E₂), sex hormone binding globulin, estradiol/total testosterone ratio (E₂/T) were analyzed. Depressive symptoms were evaluated by “beck depression inventory” (BDI), and significant depression was considered if BDI?≥?16.Thirty-four (80%) presented low TT levels, but only 4 (14%) had low free testosterone and hypogonadism symptoms; 12 of 43 (28%) presented increased E₂. Forty five (56%) presented depressive symptoms, but 16 (28% of the 45) had significant depression. BDI correlated positively with E₂ (r?=?0.407; p?=?0.001) and E₂/T (r?=?0.473; p?=?0.001), but not TT or FT. Patients with significant depressive showed higher levels of estradiol (136?±?48 versus 103?±?48?pg/ml, p?=?0.02) and E₂/T (16.0?±?9.9 versus 9.8?±?4.6; p?=?0.002) (mean?±?SD).In conclusion, obese men may present relatively excess of estradiol and deficiency in testosterone, leading to an imbalance between these two hormones. The greater this imbalance, the more depressive symptoms had our patients.     

Testosterone supplementation's effects on age-related bladder remodeling – experimental study in rats

Abstract

Objective: This study was designed to evaluate the effect of testosterone replacement on the fibrotic process of the detrusor bladder muscle during the normal aging process.

Methods: 15 Wistar senile rats, aged between 18 and 20 months were divided into two groups: testosterone group – 11 animals submitted to the administration of testosterone undecanoate (50?mg/kg intramuscular), once per month; and, Control group – four animals underwent a sham procedure. At the end of eight weeks, animals from both groups were sacrificed; bladders were removed and subsequently stereologically evaluated to determine the volumetric density of collagen fibers. The success of testosterone administration was confirmed by the measurement of serum testosterone at the beginning and end of the experiment.

Results: In the replacement group, testosterone average was 3.2?ng/ml, whereas in the control group, the mean testosterone at the end of the experiment was 0.64?ng/ml (p?<?0.05). Analysis of stereological collagenous fiber showed higher density in the control group compared to the testosterone group I (56% versus 37.02%, respectively). The difference of volume concentration of collagen between both groups was statistically significant (p?<?0.000).

Conclusion: Bladder wall fibrosis was reduced in senile rats subjected to testosterone replacement.     

Dutasteride improves bone mineral density in male patients with lower urinary tract symptoms and prostatic enlargement: a preliminary study

Introduction: We studied the effect of dutasteride on bone mineral density (BMD) in aging male patients with lower urinary tract symptoms (LUTS) and prostatic enlargement.

Methods: We prospectively studied 17 patients with LUTS and prostatic enlargement. Before and 1 year after dutasteride (0.5?mg daily), we assessed International Prostate Symptom Score (IPSS), prostatic volume (PV), serum prostatic-specific antigen (PSA) and testosterone. BMD in the lumbar and femur was measured by DEXA method.

Results: Dutasteride significantly reduced PV (from 51?±?24 to 34?±?17?ml, p?p?p?2, p?2, p?2, p?Conclusions: Dutasteride has a potential to improve BMD with elevation of serum testosterone in aging male patients with LUTS and prostatic enlargement.     

Oral testosterone undecanoate (Andriol®) supplement therapy improves the quality of life for men with testosterone deficiency

In a single-blind, placebo-controlled study, the effects of a 3-month oral administration of 160 mg/day testosterone undecanoate (Andriol^®) on the quality of life of men with testosterone deficiency were evaluated. The subjects included ten men with primary hypogonadism and 29 with andropause with sexual dysfunction as the most common problem. The changes in subjective symptoms were evaluated by the PNUH QoL scoring system and the St. Louis University Questionnaire for androgen deficiency in aging males (ADAM). Digital rectal examination (DRE) was performed and serum testosterone, prostate-specific antigen (PSA) and liver profile were monitored. Testosterone undecanoate treatment (n = 33) significantly improved sexual dysfunction and symptom scores of metabolic, cardiopulmonary, musculo-skeletal and gastrointestinal functions compared to baseline and to placebo (n = 6). ADAM score also significantly improved after 3 months of treatment. Serum testosterone was significantly increased compared to pretreatment levels only in the testosterone undecanoate group. In the placebo group, no significant changes compared to baseline were found for testosterone levels and QoL questionnaires. No abnormal findings were detected on DRE or laboratory findings in either group. Adverse events, such as gastrointestinal problems and fatigue, were mild and self-limiting. It is concluded that androgen supplement therapy with oral testosterone undecanoate (Andriol) restores the quality of life through improvement of general body functions in men with testosterone deficiency.     

The effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism

Objectives: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH).

Methods: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4?ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT.

Results: The mean serum total testosterone significantly increased from 178.04?±?51.92 to 496.28?±?103.73?ng/dl (p?=?0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT.

Conclusions: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT.     

A four-year efficacy and safety study of the long-acting parenteral testosterone undecanoate

Introduction. This is a four-year follow-up of 25 men who received parenteral testosterone undecanoate (TU), 1000 mg every 12 weeks for at least four years. This study was a continuation of a 30-week study wherein the effects of TU had been compared to those of parenteral testosterone enanthate.

Methods & Results. Plasma testosterone (T) trough values of the injection interval of 12 weeks): median 11.9 – 15.9 nmol/L (N 10.0–30.0). E2 and SHBG were stable. Body weight, BMI, waist-to-hip ratio remained stable. Total cholesterol, and triglycerides were unchanged but plasma LDL declined while HDL, after an initial reduction over the first 30 weeks, had increased significantly after three years. Leptin levels, bone mineral density, blood pressure, liver function tests, haemoglobin and haematocrit levels remained stable without values above the upper limit of normal. Over the first 12 months of the study there was an increase in prostate volume from 19.7 ± 8.8 mL to 22.0 ± 8.4 mL (p < 0.05) but thereafter volumes remained stable, paralleled by an increase in PSA from 0.67 ± 0.38 µg/dL to 0.75 ± 0.35 µg/dL (p < 0.05) without any further changes after 12 months.

Conclusion. TU appears to be a stable and safe treatment modality of hypogonadal men.     

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.     

Evaluation of sex hormone levels and some metabolic factors in men with coronary atherosclerosis

Background Because of the great controversy over the role of androgens in the pathogenesis of atherosclerosis, we investigated the relationship between serum sex hormone levels and angiographically confirmed coronary artery disease in men.

Material and methods We investigated 86 men aged 40–60 years, 56 with coronary artery disease and 30 healthy men, matched by age, as a control group. Body mass index and waist to hip ratio were calculated and total body fat mass and percentage of abdominal deposit were investigated by dual-energy X-ray absorptiometry (Dpx (?+?) Lunar, USA). The serum levels of sex hormones and insulin were measured using commercial radioimmunoassay and IRMA (by SHBG) kits (DPC, USA). The serum levels of lipids and glucose were assessed by means of enzymatic methods.

Results Men with coronary artery disease had lower total testosterone levels (17.01?±?6.42 vs. 19.37?±?6.58?nmol/l; p?<?0.05), testosterone/estradiol ratio (228.5?±?88.5 vs. 289.8?±?120.1; p?<?0.05) and free androgen index (FAI) (59.49?±?14.79 vs. 83.03?±?25.81; p?<?0.0001), and higher levels of estrone (49.5?±?27.7 vs. 36.6?±?12.7?pg/ml) than men in the control group. Moreover, men with coronary artery disease were more insulin-resistant than controls and had an atherogenic lipid profile. There was an inverse correlation (p?<?0.05) between testosterone level and serum level of glucose (r?=??0.29), triglycerides (r?=??0.37), body mass index (r?=??0.55), waist (r?=??0.43), total body fat mass (r?=??0.3) and fasting insulin resistance index. A significant positive association (p?<?0.05) was found between testosterone and the quantitative insulin sensitivity check index and high density lipoprotein cholesterol level in serum (r?=?0.26).

Conclusions Low levels of total testosterone, testosterone/estradiol ratio and free androgen index and higher levels of estrone in men with coronary artery disease appear together with many features of metabolic syndrome and may be involved in the pathogenesis of coronary atherosclerosis.     

Effect of cigarette smoking on sexual functions,psychological factors,and disease activity in male patients with ankylosing spondylitis

Objective: This study aims to investigate the effect of smoking on sexual functions in AS patients.

Patients and methods: A total of 67 male AS patients with a median age of 34 years (range: 18–57) reporting sexual activity at least for the past 4 weeks period were included. Patients were divided into smokers (Group 1, n?=?47) and non-smokers (Group 2, n?=?20). Fagerström test for nicotine dependence, smoking history, exhaled carbon monoxide test were recorded for smoking AS patients. Visual analogue scale (VAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Quality of Life (ASQoL), International Index of Erectile Function (IIEF), Beck Depression Inventory (BDI) were filled for both groups.

Results: There was no significant difference between smokers and non-smokers in all evaluation parameters. BASMI scores were significantly lower in the mild dependency subgroup as compared to those with moderate or severe dependency (p?=?.005 and p?=?.007, respectively). Total IIEF score and IIEF categories correlated significantly with BASDAI, BASFI, BASMI, ASQoL, pain, fatigue, and cumulative smoking. BDI showed an inverse correlation with the IIEF score and IIEF category (p?r?=?–0.520, p?r?=?–0.508, respectively).

Conclusions: Sexual function in AS patients is associated with the pain, fatigue, disease activity, functional status, quality of life, depression as well as the cumulative exposure to smoking, and that sexual functions tend to decline with increasing degree of cigarette dependency.     

Clinical experience with the new long-acting injectable testosterone undecanoate. Report on the educational symposium on the occasion of the 5th World Congress on the Aging Male, 9–12 February 2006, Salzburg,Austria

This symposium report summarizes first extensive clinical findings with injectable testosterone undecanoate (Nebido®) in hypogonadal patients showing clinical symptoms of androgen deficiency with or without erectile dysfunction (ED). This new testosterone formulation (1000 mg testosterone undecanoate in 4 ml castor oil) possesses nearly ideal long-term kinetics, i.e. sustained close mimicking of eugonadal testosterone serum levels without supra- or sub-physiological serum concentrations. The generally accepted administration scheme recommends the second injection 6 weeks after the first one followed by further injections every 12 weeks. Applying this regimen, administration intervals are drastically reduced in comparison to conventional i.m. testosterone preparations (e.g. about 16 injections of testosterone enanthate vs. 4–5 injections of testosterone undecanoate per year). Depending on the testosterone serum levels, individualized therapy is possible by shortening (every 10 weeks) or prolonging (every 14 weeks) the injection intervals. In hypogonadal patients with ED 58% respond to testosterone undecanoate alone. Best results are seen in diabetic hypogonadal patients. The regimen of injectable testosterone undecanoate administration ideally fits recommendations regarding pharmacokinetics, efficacy and safety monitoring.     

Treatment with human chorionic gonadotropin for PADAM: A preliminary report

The purpose of this study was to evaluate the efficacy and safety of human chorionic gonadotropin (hCG) for patients with partial androgen deficiency of the aging male (PADAM). Twenty-one patients over 50 years of age with PADAM symptoms were included in this study. Laboratory and endocrinologic profiles were reviewed as appropriate, and PADAM symptoms were judged by means of several questionnaires such as the Aging Males' Symptoms (AMS) scale, short version of the International Index of Erectile Function (IIEF-5), and the Self-rating Depression Scale (SDS). Laboratory and endocrinologic values and symptom scores were evaluated and compared before and after treatment by hCG injection. The treatment period was 8.0 ± 5.0 months (3.0 – 24.0 months). Serum concentrations of testosterone, including total testosterone, calculated free testosterone, and calculated bioavailable testosterone, increased significantly. AMS total scores and subscores decreased significantly after treatment. However, IIEF-5 and SDS scores did not improve. With respect to adverse effects, laboratory tests showed that only red blood cell count, hematocrit and hemoglobin level increased significantly after treatment, however, these values remained within the normal range. No adverse effect was identified after treatment. We conclude that hCG injection may be considered as a treatment for PADAM.