F. Saad

An Exploratory Study of the Effects of 12 Month Administration of the Novel Long-Acting Testosterone Undecanoate on Measures of Sexual Function and the Metabolic Syndrome

Administration of testosterone undecanoate (TU) over 12 months to men with sexual dysfunction and signs of the metabolic syndrome, restored their plasma testosterone (T) levels to the mid-range of reference values. This had a beneficial effect on their sexual functioning as evidenced by an improvement of their scores on the International Index of Erectile Function. The scores on the Aging Male Symptoms score, AMS, were also improved. Most impressive were the improvements in the parameters of the metabolic syndrome; they all improved and appeared largely correlated (i.e., decline in waist circumference with declines of plasma cholesterol and LDL and increase in plasma HDL). Sex hormone binding globulin, SHBG, may be considered as an indicator of the severity of the metabolic syndrome; levels of SHBG initially fell, probably as a result of rising plasma T levels. But over the last six months of the observation period when plasma T rose further, there was a significant increase in plasma SHBG which may be interpreted to indicate an improvement of the metabolic syndrome. Blood pressure improved slightly but significantly. In this cohort of elderly men (54–76 years; median 64 years) there were no safety concerns over a one year period of T administration. Prostate specific antigen, PSA, levels remained stable; the International Prostate Symptoms Score, IPSS, improved slightly. Liver functions and plasma glucose remained stable. Hemoglogin and hematocrit values increased significantly but remained within reference values.

Effects of testosterone gel followed by parenteral testosterone undecanoate on sexual dysfunction and on features of the metabolic syndrome

The effects of administration of testosterone (T) gel, resulting in plasma T levels in the low range of reference values, followed by testosterone undecanoate (TU), producing plasma T levels in the mid‐normal range, were measured in 27 hypogonadal men aged 47–74u2003years. T gel had positive effects on the International Index of Erectile Function, the Aging Males’ Symptoms Scale and International Prostate Symptoms Score and on the metabolic syndrome. The improvement was larger when TU was administered and plasma T levels were higher. The reduction in waist circumference and plasma cholesterol were larger with TU than with T gel, while the increases in plasma high‐density lipoprotein and sex hormone binding globulin (an indicator of the severity of the metabolic syndrome) were larger with TU than with T gel. Both T gel and TU appeared safe on prostate parameters. Plasma haemoglobin and haematocrit were elevated but remained in the normal range. The assumption that treatment with T is adequate when achieved plasma levels of T are within the reference range is no longer tenable. Some androgen‐dependent biological functions require higher plasma T levels than others, and, moreover, these thresholds differ among men.

Men with testosterone deficiency and a history of cardiovascular diseases benefit from long-term testosterone therapy: observational, real-life data from a registry study.

Background/objectives Long-term testosterone therapy (TTh) in men with hypogonadism has been shown to improve all components of the metabolic syndrome. In this study, we investigated the effects of long-term TTh up to 8 years in hypogonadal men with a history of cardiovascular disease (CVD). Patients and methods In two urological clinics observational registries, we identified 77 hypogonadal men receiving TTh who also had a history of CVD. The effects of TTh on anthropometric and metabolic parameters were investigated for a maximum duration of 8 years. Any occurrence of major adverse cardiovascular events was reported. All men received long-acting injections of testosterone undecanoate at 3-monthly intervals. Results In 77 hypogonadal men with a history of CVD who received TTh, we observed a significant weight loss and a decrease in waist circumference and body mass index. Mean weight decreased from 114±13 kg to 91±9 kg, change from baseline: −24±1 kg and −20.2%±0.5%. Waist circumference decreased from 112±8 cm to 99±6 cm, change from baseline: −13±0.3 cm. Body mass index decreased from 37±4 to 29±3, change from baseline: −8±0.2 kg/m2. Cardio-metabolic parameters such as lipid pattern, glycemic control, blood pressure, heart rate, and pulse pressure all improved significantly and sustainably. No patient suffered a major adverse cardiovascular event during the full observation time. Conclusion In men with hypogonadism, TTh appears to be effective in achieving sustained improvements in all cardiometabolic risk factors and may be effective as an add-on measure in the secondary prevention of cardiovascular events in hypogonadal men with a history of CVD.

Decline of plasma 5α-dihydrotestosterone (DHT) levels upon testosterone administration to elderly men with subnormal plasma testosterone and high DHT levels

The study was performed to measure the impact of testosterone (T) administration on circulating levels of 5α‐dihydrotestosterone (DHT). Group 1 (32 men; mean age 61u2003years; mean T 6.9u2003±u20031.9u2003nmolu2003l−1) were treated for 15u2003months with long‐acting T undecanoate. Group 2 (23 men, mean age 60u2003years, mean T 7.6u2003±u20032.0u2003nmolu2003l−1) were treated for 9u2003months with T gel. Plasma T and DHT were measured before and after 9u2003months T administration. In the men treated with T undecanoate plasma T and DHT were also measured after 12 and 15u2003months. Before T administration, plasma DHT ranged from 0.39 to 1.76u2003nmolu2003l−1 (0.30–1.90u2003nmolu2003l−1). Mean DHT declined upon T administration from 0.95u2003±u20030.50 to 0.55u2003±u20030.30u2003nmolu2003l−1 (Pu2003<u20030.05). With an arbitrary cut‐off at 0.60u2003nmolu2003l−1, all 21 values of DHT > 0.60u2003nmolu2003l−1 had fallen from 1.29u2003±u20030.50 to 0.70u2003±u20030.60u2003nmolu2003l−1 (Pu2003<u20030.01). Below this cut‐off point 13 values rose and 21 fell upon T administration. Below this cut‐off point values on average declined from 0.39u2003±u20030.12 to 0.30u2003±u20030.14u2003nmolu2003l−1 (Pu2003<u20030.05). The study revealed that in a cohort of elderly men with subnormal plasma T levels plasma DHT levels declined upon T administration when they were in the higher range of normal (>0.6u2003nmolu2003l−1), with a profound shift of DHT/T ratios presumed to be an indicator of a reduced 5α‐reductase activity. Below plasma DHT levels of 0.6u2003nmolu2003l−1, responses of plasma DHT to T administration varied.

Dynamic Patterns of Testosterone Levels in Individuals and Risk of Prostate Cancer among Hypogonadal Men: A Longitudinal Study

Purpose: We investigated whether dynamic patterns of testosterone levels contribute to risk of prostate cancer. Materials and Methods: We used data on 376 untreated men with hypogonadism (testosterone 12.1 nmol/l or less) recruited from a urology office in Germany. Age at study entry served as a surrogate for age at the first detection of testosterone below 12.1 nmol/l. We derived 3 indicators, including the coefficient of variation, the ratio of the largest decline relative to the mean and the median of maximum declines, to measure the dynamic patterns of testosterone in an individual. Results: Our findings suggest that the later that testosterone dropped below 12.1 nmol/l in a man, the less the lifetime risk of prostate cancer in that individual (HR 0.68, 95% CI 0.57–0.82). Further declines or dynamic variations of testosterone were associated with increased risk of prostate cancer (high vs low coefficient of variation HR 4.88, 95% CI 1.97–12.08, high vs low ratio of largest decline relative to mean HR 8.45, 95% CI 2.82–25.37 and high vs low median of maximum declines HR 2.70, 95% CI 1.15–6.35). Conclusions: To our knowledge this study is the first to provide evidence of the association between dynamic patterns of testosterone and prostate cancer development. This may have substantial clinical impacts on prostate cancer prevention.

The association of sex hormone-binding globulin with mortality is mediated by age and testosterone in men with type 2 diabetes

Serum sex hormone‐binding globulin levels have been associated with mortality in adult men with type 2 diabetes (T2DM).

Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism)

Since the early 1990s, it has been recognized that testosterone (T) levels are lower in men with type 2 diabetes mellitus (T2DM) compared with nondiabetic men (controls). Hypogonadism has been reported in approximately 50% of men with T2DM with robust correlations with measures of obesity, such as waist circumference and body mass index (BMI). In longitudinal studies, hypogonadism has been identified as a predictor of incident T2DM. Experimental withdrawal of T led to acute decreased insulin sensitivity, which can be reversed by normalization of T concentrations. Androgen deprivation therapy, commonly used in men with advanced prostate cancer, increases the risk of incident T2DM significantly.While short-term studies of T therapy in hypogonadal men with T2DM show only minor effects, long-term administration of T leads to meaningful and sustained improvements of glycemic control with parallel reductions in body weight and waist circumference. The more insulin-resistant and obese a patient is at the time of initiation of T therapy, the more improvements are noted. The observed effects are likely mediated by the increase in lean body mass invariably achieved by T therapy, as well as the improvement in energy and motivation, referred to as the psychotropic effects of T. As recommended by various guidelines, measuring T levels and, if indicated, restoring mens T levels into the normal physiological range can have a substantial impact on ameliorating T2DM in hypogonadal men.