Low testosterone levels in men at age 31 associates with future risk of prediabetes and type 2 diabetes: A birth cohort study.

Testosterone, the predominant sex hormone in men, is produced by the testes under stimulation by the gonadotrophs in the pituitary, which in turn are controlled by gonadotropin-releasing hormone neurons in the hypothalamus. A young adult man generally produces 3 to 10 mg of testosterone daily, which translates into serum values of 300 to 1000 ng/dL. The consequences of classical male hypogonadism (primary or secondary) have been long known to physicians and patients alike and include decreased libido, erectile dysfunction, osteoporosis, reduced sexual hair, and changes in body habitus. Recently, we have come to appreciate that reductions in serum testosterone resulting from aging or chronic disease have signs and symptoms similar to those seen in classical male hypogonadism, along with increased fat mass, decreased lean body mass, decreased muscle strength, and diminished quality of life.1 During the past decade, reports have been trickling in, mainly from laboratory and epidemiological studies (and a few clinical studies), linking differences in serum testosterone levels to various cardiovascular risk factors and also directly to cardiovascular disease and death. The article by Khaw et al2 in this issue of Circulation is another link to this growing chain. Article p 2694 Thirteen years ago, Phillips et al3 reported that low total and free testosterone levels were inversely linked to coronary artery disease, even after adjusting for age and adiposity. This observation still holds true, as was recently supported by a study showing that men with angiographically proven coronary artery disease had lower levels of testosterone than those of controls.4 Furthermore, testosterone levels were negatively correlated to the degree of coronary involvement. A few population-based studies have been published that relate low serum testosterone level with risk of death. A study of male veterans showed that low testosterone was associated with increased risk of …

Insulin resistance is associated with metabolic syndrome and type 2 diabetes, representing a risk factor for cardiovascular disease. This relationship may be modulated to some extent by age-related changes in sex hormone status. We examined whether lower testosterone or sex hormone-binding globulin (SHBG) levels in older men are associated with insulin resistance independently of measures of central obesity. Cross-sectional analysis of 2470 community-dwelling non-diabetic men aged > or = 70 years. Age, body mass index (BMI) and waist circumference were measured. Early morning sera were assayed for total testosterone, SHBG, LH and insulin levels. Free testosterone was calculated using mass action equations, and insulin resistance was assessed using a homeostatic model (HOMA2-IR). Total testosterone, free testosterone and SHBG declined progressively across increasing quintiles of HOMA2-IR (all P<0.001) and correlated inversely with log HOMA2-IR (r=-0.27, -0.14 and -0.24 respectively, all P<0.001). After adjusting for age, BMI, waist circumference, high-density lipoprotein and triglyceride levels, total testosterone was independently associated with log HOMA2-IR (beta=0.05, P<0.001), while SHBG was not. Serum total testosterone <8 nmol/l was associated with HOMA2-IR in the highest quintile (odds ratio (OR) 1.67, 95% confidence interval (CI) 1.02-2.73) as was total testosterone > or = 8 and <15 nmol/l (OR 1.29, 95% CI 1.03-1.63). In older men, lower total testosterone is associated with insulin resistance independently of measures of central obesity. This association is seen with testosterone levels in the low to normal range. Further studies are needed to evaluate interventions that raise testosterone levels in men with reduced insulin sensitivity.

The paper by San Francisco et al. 1 in this issue of BJUI, reviews 154 patients with prostate cancer who were included in an active surveillance cohort. In all, 54 (35%) progressed to active treatment. Men who had disease reclassification had significantly lower free testosterone than those who were not reclassified. They concluded that on multivariate analysis, free testosterone and a family history of prostate cancer were independent predictors of disease reclassification. The authors acknowledge that this was a retrospective study of small size and the data was missing in some of the men, sex hormone-binding globulin (SHBG), luteinizing hormone and oestradiol were not measured. Nevertheless, this review adds to the increasing evidence that it is important to measure testosterone levels in men with prostate cancer. Previous studies have indicated that a low testosterone level before treatment for prostate cancer is an independent predictor of a more aggressive high-grade cancer 2. In addition to this, there appears to be an increased likelihood of extraprostatic disease at the time of diagnosis 3 and an unfavourable response to treatment 4. Garcia-Cruz et al. 5 in 2012 reported that low testosterone bioavailability is related to a positive prostate cancer diagnosis in patients submitted for prostate biopsy. In a further study, he showed that low testosterone levels were related to poor prognosis factors in men with prostate cancer prior to treatment. Testosterone was inversely related to prostate cancer bilaterally and percentage of tumour in the biopsy. Higher testosterone levels were found in patients allocated to the low-risk progression group. In the multivariate analysis, older age and lower testosterone levels were related to a higher D'Amico risk of progression 5. The researchers went on to show that higher SHBG and lower bioavailable testosterone are related to prostate cancer detection on biopsy. The study was a prospective analysis of 279 patients referred for prostate biopsy. Low bioavailable testosterone and high SHBG levels were related to a 4.9- and 3.2-fold increased risk of detection of prostate cancer on prostate biopsy taken due to an abnormal PSA result or an abnormal DRE 6. Free testosterone accounts for about 1–2% of total testosterone and hence most circulating testosterone is bound to SHBG and as such, is inactive. Yamamoto et al. 7 had previously shown that men with a low free testosterone (<1.5 ng/dL) had an increased risk of a high Gleason score (>8) compared with men with higher free testosterone (8% vs 2%; P = 0.04). Additionally, a free testosterone level of <1.5 ng/dL was associated with increased risk of biochemical recurrence of tumour. Morgentaler et al. 8 have been turning conventional wisdom upside down. They report on 13 symptomatic testosterone deficient men who also had untreated prostate cancer. The men received testosterone therapy while undergoing active surveillance for a median of 2.5 years. None of the men had aggressive or advanced prostate cancer and they were rigorously followed up. Despite effective treatment, neither the PSA level nor prostate volume showed any change. Follow-up biopsies were taken in all of the men at yearly intervals and none developed cancer progression. It is intriguing to think that the decline in testosterone with age and comorbidities may contribute to tumorigenesis in the prostate. Clearly this study needs to be replicated with much larger numbers. But it seems reasonable to suggest that we ought to know about the hormonal environment existing in our patients with prostate cancer. This will of course, raise the even more controversial area of what to do about men with symptomatic hypogonadism with treated and untreated prostate cancer. There is limited data available on this issue. Before considering testosterone therapy, the first step should be intensive lifestyle intervention; this is not only known to improve cancer survival, but raises total and free testosterone. Weight loss inhibits aromatase, and other complex cytokines, this reduces the suppression of the pituitary gonadal axis and conversion of testosterone to oestrogen, raising testosterone levels. M.K. has received funding for research, conference attendance, lecturing and advice from the pharmaceutical industry.

Fatty liver disease genetic risk variants and interference on sex hormones.

The results of recent studies suggest that a relative hypogonadism in men is associated with several established risk factors for prevalent diseases. Therefore, we determined total and free testosterone, luteinizing hormone (LH), and sex-hormone binding globulin (SHBG) in a cohort of randomly selected men (n = 659) at 67 years of age. These data were analyzed cross-sectionally in relation to blood glucose and serum insulin, which were measured while fasting and after an oral glucose tolerance test, in addition to plasma lipids and blood pressure. The data were also analyzed in relation to impaired glucose tolerance (IGT) and diabetes, which were discovered at examination or earlier diagnosis. Risk factors for the development of diabetes up to 80 years of age were analyzed with univariate and multivariate statistics. Total and free testosterone and SHBG concentrations correlated negatively with glucose and insulin values; total testosterone and SHBG, with triglycerides; and SHBG, with blood pressure (from P < 0.05 to P < 0.01). Men with IGT or newly diagnosed diabetes had higher BMI values (26.2 +/- 0.31 and 27.0 +/- 0.59 [mean +/- SE], respectively) and waist circumference (99.0 +/- 1.03 and 100.5 +/- 1.57) than nondiabetic men (BMI, 25.1 +/- 0.14; waist circumference, 95.4 +/- 0.47; P < 0.05), indicating abdominal obesity. Such men and men with previously diagnosed diabetes had, in general, lower total and free testosterone and SHBG levels, while those for LH were not different. In multivariate analyses that included BMI, waist-to-hip ratio, total and free testosterone, and SHBG, the remaining independent predictors for the development of diabetes were low total testosterone (P = 0.015) and, on the borderline, low SHBG (P = 0.053). In relation to nondiabetic men, the risk ratio for mortality, myocardial infarction, and stroke increased gradually and significantly from 1.18 to 1.68, from 1.51 to 1.78, and from 1.72 to 2.46 in men with IGT, newly diagnosed diabetes, and previously known diabetes, respectively. It was concluded that low testosterone and SHBG concentrations in elderly men are associated with established risk factors for diabetes and in established diabetes. Moreover, low testosterone levels independently predict the risk of developing diabetes. In different degrees of expression, the diabetic state predicts strongly (and gradually mortality from) myocardial infarction and stroke. It has been suggested that a relative hypogonadism might be a primary event, because other studies have shown that testosterone deficiency is followed by insulin resistance, which is ameliorated by testosterone substitution. The data suggest that the relative hypogonadism involved might be of both central and peripheral origin.

To study the impact of endogenous sex hormone levels in community-dwelling men on later risk for type 2 diabetes. Population-based prospective cohort study. For the analyses, 1454 men who participated in the fourth Tromsø study (1994-1995) were used. Cases of diabetes were retrieved and validated until 31.12.05 following a detailed protocol. The prospective association between sex hormones and diabetes was examined using Cox proportional hazard regression analysis, allowing for multivariate adjustments. There was a significantly lowered multi-adjusted risk for later diabetes with higher normal total testosterone levels, both linearly per s.d. increase (hazard ratio (HR) 0.71, confidence interval (CI) 0.54-0.92) and in the higher quartiles of total testosterone than in the lowest quartiles (HR 0.53, CI 0.33-0.84). A reduced multi-adjusted risk for incident diabetes was also found for men with higher sex hormone-binding globulin (SHBG) levels, both linearly per s.d. increase (HR 0.55, CI 0.39-0.79) and when comparing the third (HR 0.38, CI 0.18-0.81) and the fourth quartile (HR 0.37, CI 0.17-0.82) to the lowest quartile. The associations with total testosterone and SHBG were no longer significant after inclusion of waist circumference to the multivariate models. Estradiol (E(2)) was positively associated with incident diabetes after multivariate adjustments including waist circumference when comparing the second (HR 0.49, CI 0.26-0.93) and the third (HR 0.51, CI 0.27-0.96) quartile to the highest quartile. Men with higher E(2) levels had an increased risk of later diabetes independent of obesity, while men with lower total testosterone and SHBG had an increased risk of diabetes that appeared to be dependent on obesity.

BACKGROUND Total testosterone (TT) levels in males decrease with age. There has been a vigorous debate on the extent to which low testosterone causally contributes to diabetes and its complications. The aim of the present study was to determine the relationship between sex hormones and blood glucose levels in adult males. METHODS A cross-sectional study involving 259 males aged 41 - 70 years was conducted at Cilandak Subdistrict, South Jakarta. Sex hormone binding globulin (SHBG) and testosterone levels were measured by means of electro–chemiluminescent immunoassay (ECLIA), while blood glucose levels were measured enzymatically using a spectrophotometer. Free testosterone index (FTI) and body massa index (BMI) were calculated. Inter-variable relationships were tested by Pearson correlation analysis, followed by multiple linear regression analysis to determine the most influential factor on fasting blood glucose levels. RESULTS BMI was positively correlated with fasting blood glucose, but the correlation was statistically not significant (r=0.105; p=0.106). In contrast, total testosterone (TT) (r=-0.258; p=0.000) and SHBG (r=-0.193; p=0.02) had a significant negative correlation with fasting blood glucose level. Multiple linear regression showed that TT was the most influential factor on fasting blood glucose level (â=-0.044; p=0.008). CONCLUSIONS Low total testosterone level may increase fasting blood glucose level in adult males. SHBG levels did not predict fasting blood glucose levels.Assessment of testosterone in middle-aged men may allow early intervention for diabetes mellitus.

(084) Low Serum Testosterone is Associated with an Increased Risk of First-time Nephrolithiasis in Men Without Testosterone Replacement Therapy

The reported prevalence of low testosterone among men with type 2 diabetes mellitus (T2DM) is high. However, there is a dearth of information on the prevalence of androgen deficiency symptoms and low serum testosterone levels in men with T2DM from sub-Saharan Africa. Scanty data are available from Nigeria, Ghana and South Africa (SA). To determine the prevalence of low serum testosterone and associated risk factors and the prevalence of androgen deficiency symptoms in men with T2DM. In a cross-sectional observational study, androgen deficiency symptoms in men with T2DM attending two outpatient diabetes clinics in Durban, KwaZulu-Natal Province, SA, were assessed using the Ageing Males' Symptoms Scale (AMS) questionnaire and direct enquiry. Serum total testosterone (TT), sex hormone-binding globulin (SHBG), luteinising hormone (LH), fructosamine, serum lipids and glycated haemoglobin (HbA1c) were measured and free testosterone (FT) was calculated. TT, SHBG and FT levels were measured in control subjects with no history of diabetes. There were 148 men with T2DM in the study group and 50 control subjects in the control group. In the study group, the majority were black Africans (58.8%); Indians (39.2%) and whites (2.0%) constituted the remainder. The mean (standard deviation (SD)) age was 57.5 (11.2) years, the mean duration of diabetes 11.4 (8.9) years and the mean HbA1c 8.6% (1.9%). Of the study group, 85.8% had metabolic syndrome. Mean TT, SHBG and FT and median LH (interquartile range) in the study group were within normal ranges. However, mean (SD) serum TT and FT were lower in the study group than in the control subjects (14.5 (5.8) v. 18.8 (7.2) nmol/L; p&lt;0.001 and 265.9 (90.4) v. 351.7 (127.3) pmol/L; p&lt;0.001, respectively). The prevalence of low serum total testosterone (LSTT) and low serum free testosterone (LSFT) in the study group was 35.8% and 16.2%, respectively. The prevalence of androgen deficiency symptoms using the AMS questionnaire was 74.5% and correlated poorly with LSTT or LSFT. In multivariate analysis, LSFT was significantly associated with age (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.02 - 1.218; p=0.043) and waist circumference (WC) (OR 1.033, 95% CI 0.999 - 1.068; p=0.059). LSTT was associated with body mass index (BMI) only (OR 1.138, 95% CI 1.063 - 1.218; p&lt;0.0001). TT correlated inversely with BMI, WC and the number of metabolic syndrome criteria. FT correlated inversely with BMI, WC and WHR. There was a high prevalence of LSTT, LSFT and androgen deficiency symptoms in this study. Serum TT and FT were lower in men with T2DM than in control subjects. Risk factors associated with LSFT or LSTT included higher BMI and WC and older age. The AMS score was a poor predictor of low testosterone. More research is required locally before any screening policy can be recommended.

The Impact of Testosterone Therapy in Men on Cardiovascular Risk: Don’t Be Too Quick to Condemn

Men with obesity, the metabolic syndrome, and type 2 diabetes have low total and free testosterone and low sex hormone–binding globulin (SHBG). Conversely, the presence of low testosterone and/or SHBG predicts the development of metabolic syndrome and type 2 diabetes. Visceral adiposity present in men with low testosterone, the metabolic syndrome, and/or type 2 diabetes acts through proinflammatory factors. These inflammatory markers contribute to vascular endothelial dysfunction with adverse sequelae such as increased cardiovascular disease (CVD) risk and erectile dysfunction. This review focuses on the multidirectional impact of low testosterone associated with obesity and the metabolic syndrome and its effects on erectile dysfunction and CVD risk in men with type 2 diabetes. Whenever possible in this review, we will cite recent reports (after 2005) and meta-analyses. ### Epidemiological studies of low testosterone, obesity, metabolic status, and erectile dysfunction Epidemiological studies support a bidirectional relationship between serum testosterone and obesity as well as between testosterone and the metabolic syndrome. Low serum total testosterone predicts the development of central obesity and accumulation of intra-abdominal fat (1–3). Also, low total and free testosterone and SHBG levels are associated with an increased risk of developing the metabolic syndrome, independent of age and obesity (1–3). Lowering serum T levels in older men with prostate cancer treated with androgen deprivation therapy increases body fat mass (4). Conversely, high BMI, central adiposity, and the metabolic syndrome are associated with and predict low serum total and to a lesser extent free testosterone and SHBG levels (1–3,5). Because obesity suppresses SHBG and as a result total testosterone concentrations, alterations in SHBG confound the relationship between testosterone and obesity. Low total testosterone or SHBG levels are associated with type 2 diabetes, independent of age, race, obesity, and criteria for diagnosis of diabetes (6,7). In longitudinal studies, low serum total and free testosterone …

Background and Objective: Prostate cancer is one amongst the most common medical diseases affecting elderly men. Carcinoma of the prostate is being the most common non-cutaneous cancer diagnosed. The lifetime risk of prostatic carcinoma is 16.7 % and the risk of death during the entire lifetime is around 2.6% for men but the overall lifetime risk of death due to prostate malignancy is low in comparison to lifetime risk of diagnosis. Prostate cancer is a hormone dependant cancer and the clinical course of prostate cancer varies with individual and again it varies within the individual in relationship to serum testosterone levels. The present study is to find out the role of low serum testosterone level in predicting prostate cancer behaviour in comparison with normal serum testosterone level patients and to find out the relationship between low serum testosterone level and serum PSA levels in TRUS biopsy proven cancer prostate patients. The primary aim and objective of our study is to determine the association of low serum testosterone and prostate cancer behaviour and with a Secondary objective to determine the relationship of serum PSA level in cancer prostate patients with low serum testosterone. Methodology: Informed consent was obtained from all patients. All TRUS biopsy proven caner prostate patients were enrolled to a maximum number of 100. All details were recorded. Blood investigations like serum PSA, serum testosterone and other baseline investigations were obtained. The serum determinations of Testosterone obtained between 7 – 9.30 am. The serum Testosterone levels measured by appropriate standard protocols. Patients were divided into two groups based on the serum testosterone levels. Patients with low serum testosterone levels ( 250 ng/dl) were categorized as Group B and the findings between two groups will be compared. Results: Total of 106 patients with cancer prostate were taken into our study of which 5 patients on 5 alpha reductase inhibitors and 1 patient on testosterone replacement therapy were excluded from our study and finally 100 patients were enrolled in our study of which patients with low testosterone level ( 250 ng/dl) were categorized as group B. The majority (74%) of patients in low testosterone group has got a serum PSA of more than 20 values compared with only 34% of patients in the corresponding group. P value is found to be statistically significant. Most of the patients (82.6%) in low testosterone group had a higher Gleason grade (8-10) compared to the normal testosterone group. P value is found statistically significant. Conclusion: Low total serum testosterone is associated with higher proportion of predominant Gleason pattern 4, an indicator of aggressive prostate cancer. Patients with low serum testosterone levels were associated with an increased serum PSA levels compared with patients in normal serum testosterone levels. Patients with low testosterone who were managed by radical prostatectomy had a higher proportion of positive surgical margin, extra capsular extension and seminal Vesical invasion suggesting an aggressive prostate cancer behaviour. Preoperative total testosterone should be routinely added to serum prostate specific antigen estimation to improve prostate cancer management.

Could Hormone Levels Impact the Severity of Clitoral Phimosis?

Low or high hematocrit levels are associated with increased morbidity and mortality, mediated via anemia or thromboembolic events, respectively. It is therefore important to identify factors that influence hematocrit. Although androgens are known to stimulate hematopoietic cells, it is unknown whether circulating sex steroid hormones affect hematocrit. The association between serum sex steroid hormone concentrations and hematocrit in men aged ≥ 20 years was evaluated in a cross-sectional study of 1273 men in the Third National Health and Nutrition Examination Survey (1988-1991). Outcomes were low (<10th percentile), high (>90th percentile), and mean hematocrit. Men with low free testosterone levels had a lower hematocrit than men with normal free testosterone levels (P = .03), although no relationship was found between total testosterone level and hematocrit. The relationship between sex hormone-binding globulin (SHBG) and hematocrit was complex, with both low (P < .001) and high (P = .01) SHBG levels associated with lower hematocrit in men aged ≥ 20 years and only high (P = .01) SHBG levels in men aged ≥ 50 years. The odds ratio (OR) of high vs normal hematocrit increased as total estradiol (OR, 2.84; P trend = .04) and free estradiol (OR, 2.23; P trend = .09) levels increased. In this nationally representative study of men, sex steroid hormone levels, particularly low free testosterone and high SHBG levels, were associated with lower hematocrit, and high total and free estradiol levels were associated with high hematocrit. Thus, changes in sex hormone levels with aging may contribute to the increased prevalence of anemia and thromboembolic stroke in men as they age.

The aim of our study was to assess the prevalence of clinical hypogonadism, based on both symptoms and biochemical available measures of testosterone deficiency, in men with type 2 diabetes. In a cross-sectional study of 355 type 2 diabetic men aged >30 years, total and bioavailable testosterone, sex hormone-binding globulin, BMI, and waist circumference were measured and free testosterone was calculated. Overt hypogonadism was defined as the presence of clinical symptoms of hypogonadism and low testosterone level (total testosterone <8 nmol/l and/or bioavailable testosterone <2.5 nmol/l). Borderline hypogonadism was defined as the presence of symptoms and total testosterone of 8-12 nmol/l or bioavailable testosterone of 2.5-4 nmol/l. A low blood testosterone level was common in diabetic men, and a significant proportion of these men had symptoms of hypogonadism. Overt hypogonadism was seen in 17% of men with total testosterone <8 nmol/l and 14% with bioavailable testosterone <2.5 nmol/l. Borderline hypogonadism was found in 25% of men with total testosterone 8-12 nmol/l and bioavailable testosterone between 2.5 and 4 nmol/l; 42% of the men had free testosterone <0.255 nmol/l. BMI and waist circumference were both significantly negatively correlated with testosterone levels in men, with the association being stronger for waist circumference. Testosterone levels are frequently low in men with type 2 diabetes, and the majority of these men have symptoms of hypogonadism. Obesity is associated with low testosterone levels in diabetic men.