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.     

Visceral obesity,androgens and the risks of cardiovascular disease and diabetes mellitus

The sex difference in cardiovascular morbidity is traditionally ascribed to the effects of testosterone on the lipid profile. Epidemiological studies show, however, that men with cardiovascular disease have low rather than high circulating testosterone. The factor responsible for both the higher prevalence of cardiovascular disease and the low testosterone might be visceral obesity. Men and women differ in their pattern of fat distribution. Women have predominantly gluteofemoral fat depots and men preferential abdominal/visceral depots. In puberty testosterone favors abdominal/visceral fat deposition. Visceral fat has a high metabolic turnover and the free fatty acids drain on the portal vein. With a large visceral fat depot the liver is flooded with free fatty acids inducing high levels of triglycerides and low high-density lipoprotein cholesterol, impairment of insulin metabolism and reducing insulin sensitivity. These factors contribute to the development of cardiovascular disease and diabetes type II. High insulin levels suppress sex hormone-binding globulin thus lowering circulating testosterone. The fat cell produces leptin signalling to the brain to reduce food intake and increase energy expenditure. High leptin levels suppress testosterone. Some studies suggest that testosterone supplementation reduces visceral obesity and improves cardiovascular risks but more evidence is needed.     

Estradiol in elderly men

The role of estrogens in male physiology has become more evident, as a consequence of the discovery of human models of estrogen deficiency such as estrogen resistance or aromatase deficiency. In males, testosterone is the major source of plasma estradiol, the main biologically active estrogen, only 20% of which is secreted by the testes. Plasma estrone, 5% of which is converted to plasma estradiol, originates from tissue aromatization of, mainly adrenal, androstenedione. The plasma concentration of estradiol in males is 2-3 ng/dl and its production rate in blood is 25-40 μg/24 h; both of these values are significantly higher than in postmenopausal women. Plasma levels of estradiol do not necessarily reflect tissue-level activity as peripherally formed estradiol is partially metabolized in situ; thus, not all enters the general circulation, with a fraction remaining only locally active. Of the factors influencing plasma estradiol levels, plasma testosterone is a major determinant. However, the age-associated decrease in testosterone levels is scarcely reflected in plasma estradiol levels, as a result of increasing aromatase activity with age and the age-associated increase in fat mass. Free and bioavailable estradiol levels do decrease modestly with age as does the ratio of free testosterone to free estradiol, the latter testifying to the age-associated increasewd aromatization of testosterone. Estradiol levels are highly significantly positively related to body fat mass and more specifically to subcutaneous abdominal fat, but not to visceral (omental) fat. Indeed, aromatase activity in omental fat is only one-tenth of the activity in gluteal fat. Estrogens in males play an important role in the regulation of the gonadotropin feedback, several brain functions, bone maturation, regulation of bone resorption and in lipid metabolism. Moreover, they affect skin metabolism and are an important factor determining sex interest in man.     

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.     

An audit of testosterone measurement in men attending with impotence

As part of the routine assessment of 185 unselected men with undiagnosed impotence, testosterone was measured on a single serum sample to try to detect a subset of men with androgen deficiency who might benefit from testosterone replacement therapy. Those with low levels of testosterone were investigated further with repeat measurements of testosterone and luteinizing hormone (LH). In addition, prostatic specific antigen (PSA) was measured in all the men to exclude concomitant prostate cancer. Testosterone replacement therapy was offered to 20 men with consistently low levels of the hormone but few of the men continued with the therapy because of lack of benefit. It was concluded that either testosterone deficiency is rare in unselected men who actually seek help for impotence orebe our protocol of androgen assessment was not helpful for this group of men. There was correlation between PSA results and testosterone and this may have implications for the investigation of prostate cancer. The results presented here are an audit of a clinical practice and call into question the benefit of routine testosterone measurement in the investigation of all men complaining of impotence.     

Androgen replacement therapy in aging men with secondary hypogonadism

Many animal and human studies show that supraphysiological doses of dehydroepiandrosterone (DHEA) can influence body composition and carbohydrate and lipid metabolism. Most studies have concentrated on women and have not been randomized, thus creating controversial results. With this in mind, we designed a cross-over double-blind placebo-controlled study of 12 men aged 59.0 ± 4.8 years, who received either 50 mg/24 h DHEA or placebo for 3 months to assess the influence of DHEA on the content and distribution of fat tissue and serum insulin, glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels, as well as testosterone, estradiol, DHEA-sulfate (S), prostate-specific antigen (PSA) concentrations and indexes of insulin sensitivity and resistance. Patients were recruited from university employees attending for periodic health checks, with normal hepatic and renal function with endogenous DHEA-S level < 1500 ng/dl. Our results did not reveal any significant changes in study parameters, apart from a statistically significant increase in DHEA-S levels after therapy with active substance.     

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.     

Bone mineral density in men with and without the metabolic syndrome

The objective of this study was to measure bone mineral density (BMD) in middle-aged men with and without the metabolic syndrome according to the International diabetes federation (IDF) definition from 2005. We studied 80 men (mean age: 51.9 ± 9.0 y, mean body mass index (BMI): 32.0 ± 1.7 kg/m²) with and 92 men without the metabolic syndrome (mean age: 52.6 ± 15.1 y, mean BMI: 24.9 ± 2.8 kg/m²). Height (cm), weight (kg), waist circumference (cm) and blood pressure were measured. Fasting plasma glucose (FPG) and blood lipids were determined. BMD at the lumbar spine and total hip was measured by dual X-ray absorptiometry on a Hologic QDR 4500 bone densitometer. In men around 59.3% had a waist circumference > 94 cm (abdominal obesity). Among them 58.7% showed abnormal BP values. Around 30.7% had FPG ≥ 5.6 mmol/L and 22.7% had low high density lipoprotein (HDL)-cholesterol and 36.6% had hypertriglyceridemia. In men with the metabolic syndrome, mean lumbar spine BMD was 0.986 ± 0.210 g/cm² and total hip BMD – 1.012 ± 0.209 g/cm². The corresponding values in men without this syndrome were 0.934 ± 0.179 g/cm² and 0.894 ± 0.189 g/cm², respectively. The inter-group BMD difference reached statistical significance only at the hip (p = 0.039). Respectively, the prevalence of osteoporosis at the central sites was significantly higher in men without the metabolic syndrome (MS) (13.2 versus 20.8%, p = 0.03). Our data confirmed the trend for higher BMD in the studied men with the metabolic syndrome.     

Increased prevalence of premature ejaculation in men with metabolic syndrome

This prospective study aimed to investigate the relationship between metabolic syndrome (Met S) and premature ejaculation (PE) among men. The study included 300 consecutive male patients (53.6 y?±?8.7) who attended the urology clinic (December 2013–September 2014), mostly complaining of renal/ureteric calculi. A diagnostic approach was undertaken to include demographics, clinical features and laboratory investigations of the study subjects. Both erectile function and PE were evaluated using the International Index of Erectile Function (abridged form, IIEF-5) and Premature Ejaculation Diagnostic Tool (PEDT) questionnaires, respectively. Results identified 182 (60.7%) men had Met S. Prevalence of PE was significantly higher in the subjects with Met S than the controls (35.2% vs 7.6%, p?< 0.001). Patients with Met S and PE had significantly higher PEDT scores (15.4 vs 6.7), smaller waist circumference (108.3?cm vs 111.5?cm) and higher fasting blood sugar (187?mg% vs 161?mg%) than those with no PE (p?p?=?0.047 and <0.001, respectively) with PE in Met S. In conclusion, PE has a high prevalence in Met S. Patients with Met S should be questioned about PE. Both ED and systolic hypertension may be associated with PE. Prevention of Met S should be considered, and this may be of help to decrease the prevalence of PE.     

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.     

Increased incidence of metabolic syndrome in older men with high normotension

Introduction: Hypertension and prehypertension are correlated with future cardiovascular disease (CVD) and diabetes. Whether these harmful effects of the blood pressure (BP) could be found in normotensive is of interest. Methods: In this cross-sectional study, totally 2388 normotensive older men aged 65–80 years undergoing routine health examinations were enrolled. To eliminate the influence of age on BP, subjects were initially grouped in each age stratum. Then in each age-stratum, subjects were further grouped into low, middle and high-tertile systolic BP (SBP) subgroups. Finally, all the low-tertile subgroups in each age stratum were gathered to form Group-1. Similarly, Group-2 (middle-tertile) and Group-3 (high-tertile) were also created. Metabolic syndrome (MetS) was regarded as having risks for future CVD and diabetes. Results: Age, waist circumstance (WC), fasting plasma glucose (FPG) and log triglyceride (TG) were independently and significantly correlated with SBP by multiple linear regression analysis. On the other hand, logistic regression showed that Group-3 had significant higher odds ratios (ORs) for having abnormal WC, FPG and TG. In addition, Group-3 presented a 1.55–fold OR (p < 0.001) for having MetS than Group-1. Conclusions: In normotensive older men, the risk for having MetS was significantly associated with higher SBP. Primary prevention of hypertension should be stressed.     

Erectile dysfunction is strongly linked with decreased libido in diabetic men

Erectile dysfunction frequently occurs with diabetes mellitus. A survey of diabetic men was conducted by anonymous questionnaire to investigate the associations of erectile dysfunction with various predictive factors. A total of 112 diabetic males without an obvious history of erectile dysfunction were available for analyses. The mean age and duration of diabetes were 53.7?±?12.2 years and 10.2?±?8.6 years (mean?±?standard deviation), respectively. The questionnaire included questions on the presence or absence of smoking, hypertension, libido and subjective symptoms of diabetic neuropathy that may be associated with erectile dysfunction. Analysis of the answers to the questionnaire revealed that 40% of the patients complained of erectile dysfunction (erection ‘always insufficient’). Erectile dysfunction was significantly correlated with age (p?=?0.005), but not with duration of diabetes (p?=?0.25), adjusted for age. Erectile dysfunction was also associated with sensory neuropathy and reduced libido, independently of age. The logistic regression analysis revealed that erectile dysfunction was positively associated with reduced libido and age. The odds ratio of erectile dysfunction for reduced compared to unreduced libido was 18.21, suggesting that psychogenic factors have a marked influence on erectile dysfunction. It is concluded that the presence of erectile dysfunction should be considered when symptoms related to diabetic neuropathy are observed; psychological approaches, such as sexual counseling, could be applied for the treatment of erectile dysfunction.     

Association between testosterone levels and the metabolic syndrome in adult men

Abstract

Objective: To evaluate the relationship between testosterone levels and the metabolic syndrome (MS) in men older than 45 years.

Methods: Six hundred and sixty men (45–70 years) selected from 2906 participants of a population screening for prostate cancer were included in this study. Testosterone and the components of MS were assessed in all men. MS was diagnosed according to NCEP-ATP III criteria. Triglycerides (TG)/HDL-cholesterol (chol) index was calculated.

Results: The presence of MS was inversely associated with testosterone (χ², p?<?0.001), independently of age (OR 0.802, CI 95%: 0.724–0.887, p?<?0.0001). Hypertension was the most frequent abnormality observed followed by elevated TG and waist circumference (WC). Testosterone correlated positively with HDL-chol (r: 0.14, p?<?0.0001) and negatively with body mass index (BMI)(r: ?0.29, p?<?0.0001), WC (r: ?0.26, p?<?0.0001), TG (r: ?0.20, p?<?0.0001), TG/HDL-chol (r: ?0.20, p?<?0.0001), glucose (r: ?0.11, p?=?0.005) and MS score (r: ?0.23, p?<?0.0001).

Conclusions: Our results show that in men older than 45 years, as long as testosterone levels decline, the prevalence of MS increases, independently of age. The correlations found between testosterone and four of the five components of MS, as well as with BMI and TG/HDL-chol ratio, a surrogate marker of insulin resistance, suggest considering male hypogonadism as a determinant of developmental abnormalities typical of MS.     

Serum levels of inhibin B in men of different age groups

The decline of testosterone levels in aging men is well documented. However, it is unclear to what extent the Sertoli cell marker inhibin B changes during aging. Herein we report on the determination of serum levels of inhibin B, follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone in 906 patients from 16 to 89 years of age, presenting to our department for different complaints. There was a weak but significant correlation of the levels of inhibin B with age (r = 0.064, p < 0.05). A significant negative correlation of FSH and inhibin B was documented in all age groups (r = -0.423, p < 0.01). Also, the LH levels increased significantly with low inhibin B levels (r = -0.289, p < 0.01). Testosterone levels showed no significant correlation with inhibin B. We conclude from our study that Sertoli cell function as documented by serum levels of inhibin B is stable throughout life. In addition, the ongoing correlation of FSH and inhibin levels also indicates no significant decline of Sertoli cell function in the aging male.     

Three-year follow-up of androgen treatment in hypogonadal men: preliminary report with testosterone gel

Transdermal testosterone gels represent an effective alternative to injectable testosterone preparations. Shortterm (6 months) data demonstrated positive effects on muscle, bone, fat, libido and mood. This report provides a preliminary analysis of longer-term treatment with a testosterone gel (AndroGel ? or Testogel®) in a group of men aged 19-67 years of age. The positive effects of testosterone treatment on all of the above parameters persisted in this 3-year follow-up. The benefits occurred independent of age (equally in the older and younger subjects). The positive effects of transdermal testosterone gel on bone mineral density previously identified at 6 months of treatment, continued with time. The positive effects on bone mineral density were greater in the spine than the hip. There were minimal effects on lipid levels. Levels of prostate-specific antigen (PSA) increased with testosterone treatment but, in general, remained in the normal range. Three subjects (1.8%) were shown to have elevated PSA and biopsy-proven prostate cancer. It was not possible to determine if this incidence is above the background rate. Monitoring for prostate disease through PSA measurements and digital rectal examination is recommended for hypogonadal men in the older age groups when treated with testosterone.     

Practical consequences of the validation of a mathematical model in assessment of partial androgen deficiency in the aging male using bioavailable testosterone

Partial androgen deficiency or the andropause in the aging male is a complex clinical and biochemical entity that needs to be analyzed at two levels of the constituent structure: the 'deep structure' should come to light with more intensive research, while the 'surface structure' holds the attention of investigators who focus on hormone measurements in the blood to help diagnose the andropause. In this study, it is recognized that bioavailable testosterone decreases progressively during the aging process. This physiological decline may be so important, or so close to castration levels, that aged men may experience numerous symptoms of hypogonadism. The assay for bioavailable testosterone was indirectly validated with a set of equations derived from our knowledge of the law of mass action at equilibrium, as proposed by Vermeulen and colleagues in 1999. With this mathematical model, we have shown that calculated free testosterone was highly correlated with bioavailable testosterone. It is therefore concluded that the evaluation of aged men's androgenicity should rely on at least one of these free testosterone assessments (bioavailable or calculated free testosterone) for the sake of reproducibility in the construction of the 'surface structure' of the andropause in the coming years.     

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study

We evaluated the effects of long-term testosterone replacement therapy (TRT) on the bone mineral density (BMD) in obese patients with metabolic syndrome (MS) and late-onset hypogonadism (LOH). Sixty men (mean age 57 ± 10) with low serum testosterone (T < 320 ng/dL) and MS regardless the presence of osteoporosis were enrolled. Forty men received intramuscular T-undecanoate (TU) four times/year for 36 months and 20 age-matched hypogonadal men with MS in whom T treatment was contraindicated were used as controls. Hormonal, biochemical markers, vertebral and femoral BMD by dual-energy x-ray absorptiometry were measured. At baseline, overall patients had mild osteopenia (lumbar BMD= 0.891 ± 0.097 g/cm(2); femoral BMD= 0.847 ± 0.117 g/cm(2)). TU induced a significant improvement of bone mass after 36 months (lumbar BMD=1.053 ± 0.145 g/cm(2); p < 0.002; femoral BMD=0.989 ± 0.109; p < 0.003 g/cm(2)) with a 5%/year increase and a significant reduction in hs-CRP without changes in body mass index. A direct relationship between serum T and BMD increments at the lumbar (r(2)?= 0.66, p < 0.0001) and femoral (r(2)?=0.52, p < 0.0001) sites was demonstrated. Study adherence was 50% without serious side effects. Long-term TRT in middle-aged men with LOH and MS determines a significant increase in both vertebral and femoral BMD related to increased serum T levels, probably independently from estradiol modifications.     

Three definitions of metabolic syndrome applied to a sample of young obese men and their relation with plasma testosterone

This study tested 60 men, aged <40 years, with a BMI 27–35 kg/m² to determine whether they had metabolic syndrome. The three definitions used to test this were from the National Cholesterol Education Program (NCEP), the World Health Organization (WHO) and the International Diabetes Federation (IDF). Further, the relationship between a positive definition and plasma testosterone (T) and calculated free T was analysed.

Using the above three definitions of metabolic syndrome (MetS), there was a large degree of overlap of identifying obese men as having the syndrome, but there were quantitatively significant differences as well. So, it is relevant in studies to identify which of the present definitions of the syndrome has been used. With aging there is an increasing prevalence of the syndrome and age itself might be a factor in the lower T levels encountered in these men. But low plasma total T and calculated free T were also consistent features of men <40 years with metabolic syndrome, regardless of which definition had been applied. Including low T levels in the definition of metabolic syndrome, may be helpful.     

The effect of androgen supplementation therapy on the prostate

With the recent availability of transdermal formulations, androgen supplementation therapy is increasingly being prescribed for men in their 50s and 60s. With the growing use of testosterone products, there is concern about the long-term risks of androgen supplementation therapy, particularly on the prostate. This article reviews what is known about the safety of testosterone replacement therapy in terms of the potential risks for development of symptomatic benign prostatic hypertrophy (BPH) and prostate cancer. Androgens are undoubtedly involved in the growth of benign prostatic nodules, as a permissive factor in the etiology of prostate carcinoma and in the enhancement of the growth of active prostate cancer. Their role in the initiation of either disease is less clear. Available data support the safety of such treatment in the short term. Caution is still advised in the interpretation of these findings, as the studies producing the data have involved relatively small numbers of participants. Until large, long-term, placebo-controlled studies have been conducted and analyzed, questions about the long-term safety of testosterone supplementation therapy in older men will remain.