Louis J G Gooren

Testosterone as Potential Effective Therapy in Treatment of Obesity in Men with Testosterone Deficiency: A Review

Objective: Obesity negatively affects human health. Limiting food intake, while producing some weight loss, results in reduction of lean body mass. Combined with moderate exercise it produces significant weight loss, maintains lean body mass and improves insulin sensitivity, but appears difficult to adhere to. Bariatric surgery is clinically effective for severely obese individuals compared with non-surgical interventions, but has limitations. Clinical and pre-clinical studies have implicated a role for testosterone (T) in the patho-physiology of obesity. Methods: Evidence Acquisition and Synthesis: A literature search in PubMed on the role of T in counteracting obesity and its complications. Results: Obesity per se impairs testicular T biosynthesis. Furthermore, lower-than-normal T levels increase accumulation of fat depots, particularly abdominal (visceral) fat. This fat distribution is associated with development of metabolic syndrome (MetS) and its sequels, namely type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T treatment reverses fat accumulation with significant improvement in lean body mass, insulin sensitivity and biochemical profiles of cardiovascular risk. The contribution of T to combating obesity in hypogonadal men remains largely unknown to medical professionals managing patients with obesity and metabolic syndrome. Many physicians associate T treatment in men with risks for prostate malignancy and CVD. These beliefs are not supported by recent insights. Conclusion: While overall treatment of obesity is unsuccessful, T treatment of hypogonadal men may be effective, also because it improves mood, energy, reduces fatigue and may motivate men to adhere to diet and exercise regimens designed to combat obesity.

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.

Concurrent improvement of the metabolic syndrome and lower urinary tract symptoms upon normalisation of plasma testosterone levels in hypogonadal elderly men

Central obesity in adulthood, the metabolic syndrome, erectile failure and lower urinary tract symptoms (LUTS) are all associated with lower‐than‐normal testosterone levels, although the relationship between testosterone and LUTS appears weak. The metabolic syndrome is associated with an overactivity of the autonomic nervous system. Alternatively, the metabolic syndrome is associated with markers of inflammation, such as C‐reactive protein (CRP), maybe signalling intraprostatic inflammation. A large cohort of 95 middle‐aged to elderly hypogonadal men (T levels 5.9–12.1u2003nmolu2003l−1) were treated with parenteral testosterone undecanoate and its effects on the metabolic syndrome {waist circumference, cholesterol, CRP and LUTS [residual bladder volume (RBV), International Prostate Symptoms Score (IPSS), prostate volume, prostate‐specific antigen (PSA)]} were evaluated. Along with the improvements of the metabolic syndrome, there was a significant decline of the values of the IPSS, RBV and CRP. There was a (low) level of correlation between the decline of waist circumference and residual volume of urine but not with IPSS and prostate size. Along with the improvement of the metabolic syndrome upon testosterone administration, there was also an improvement of the IPSS and of RBV of urine and CRP. The mechanism remains to be elucidated.

A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up

Introduction: The clinical significance of low to low-normal testosterone (T) levels in men remains debated. Aim: To analyze the effects of raising serum T on lean body mass (LBM), fat mass (FM), total body mass, and health-related quality-of-life (HRQoL). Methods: Randomized, double-blind, placebo-controlled study. Men, aged 50–80 years, with serum total T<15 nmol/L and bioavailable T < 6.68 nmol/L, and a Aging Males’ Symptoms (AMS) total score >36, received 6 months treatment with transdermal 1% T gel (5–7.5u2009mg/day; n =183) or placebo gel (n =179), followed by 12 months open-label with T in all. Results: After 6 months, LBM increased in T- treated patients by 1.28u2009±u20090.15u2009kg (mean ± SE) and FM decreased by 1.16u2009±u20090.16u2009kg, with minor changes with placebo (LBM +0.02u2009±u20090.10u2009kg and FM −0.14u2009±u20090.12u2009kg; all p < 0.001, T group vs. placebo). Changes were largely similar across subgroups of age, baseline total testosterone, and baseline BMI. Total HRQoL improved compared with placebo (p < 0.05, T group vs. placebo). Conclusions: Six months 1% T gel improved body composition and HRQoL in symptomatic men with low to low-normal T, with further improvements over the following 12 months.

Lower urinary-tract symptoms and testosterone in elderly men

ObjectivesThe objective was to examine the effects of testosterone administration on symptom scores of lower urinary tract symptoms (LUTS).MethodsThe literatures on the epidemiological association between the metabolic syndrome, erectile failure and (LUTS) were reviewed.ResultsIn men with the metabolic syndrome and erectile failure, often lower-than-normal testosterone levels are found. This is less clear for men with LUTS, but the relationship between testosterone and LUTS might be indirect and based on the association of the metabolic syndrome with an overactivity of autonomic nervous system. This overactivity may play a key role in increasing the severity of LUTS above an intrinsic basal intensity that is determined by the genitourinary factors in aging men. Androgen receptors are present in the epithelium of the urethra and the bladder. Testosterone may play a role in the reflex activity of the autonomic nervous system in the pelvis, or may interact with postsynaptic non-genomic receptors suppressing detrusor activity. Human neurons in the wall of the bladder contain nitric oxide synthase. Similar to the penis, testosterone has an impact on nitric oxide synthase.ConclusionsSome studies investigating the effects of normalizing testosterone levels in elderly men have found a positive effect on variables of the metabolic syndrome and, simultaneously, on scores of the International Prostate Symptoms Score (IPSS) which is worthy of further investigation in randomized, controlled and sufficiently powered clinical trials.

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.

Timetable of effects of testosterone administration to hypogonadal men on variables of sex and mood.

Introduction.u2003The effects of testosterone have been extensively characterized, but little attention has been given to the timetable of occurrence of the various effects of testosterone. Methods.u2003The timetables of effects on sexual and psychological variables in 40 hypogonadal men receiving treatment with either parenteral testosterone enanthate (TE) or undecanoate (TU). Results.u2003Sexual thoughts/fantasies and sexual interest/desire/spontaneous morning erections emerged quickly and plateaued after 3 weeks. Total erections rose to a maximum over 9 weeks and then plateaued. Ejaculations per week/satisfaction with sex life rose over the first 3 weeks, increasing steadily to a plateau at 12 weeks. Depression scores decreased to reach a plateau after 6 weeks. Aggressiveness did not change. Scores of concentration improved and reached a plateau after 3 weeks in the group treated with TE and after 9 weeks in the group treated with TU. Good mood improved after 6–9 weeks. Positive effects on self-confidence appeared between 3–6 weeks and on fatigue after 9–12 weeks. Conclusion.u2003Insight into the emergence of effects may be useful information for the patient and for the attending physician in monitoring clinical effects of testosterone treatment of hypogonadal men.

The impact of testosterone administration to female-to-male transsexuals on insulin resistance and lipid parameters compared with women with polycystic ovary syndrome

OBJECTIVEnTo evaluate the impact of testosterone (T) administration to female-to-male transsexuals (FtMs) on insulin resistance and lipid parameters and to compare the effects with women with polycystic ovary syndrome (PCOS).nnnDESIGNnCohort analysis.nnnSETTINGnUniversity hospital.nnnPATIENT(S)nTwenty-nine FtMs and 240 women with PCOS.nnnINTERVENTION(S)nScreening panel, ultrasound of the ovaries, hormone, lipid, and glucose and insulin measurements.nnnMAIN OUTCOME MEASURE(S)nEndocrine, metabolic parameters, and insulin resistance.nnnRESULT(S)nThe PCOS women had significantly higher fasting, 1-h, and 2-h insulin levels and a significantly lower insulin sensitivity index compared with FtMs before and after their T treatment. There were higher triglyceride levels and lower high-density lipoprotein cholesterol levels upon T treatment in FtMs compared with the PCOS women. Women with PCOS had higher body mass index (BMI) values. Positive correlations between insulin resistance indices and BMI were found only in women with PCOS.nnnCONCLUSION(S)nTestosterone administration by itself showed little detrimental influence on insulin resistance indices, but it had significant effects on lipid profiles. Compared with T, BMI had a greater impact on insulin resistance in women with PCOS.

A safety study of administration of parenteral testosterone undecanoate to elderly men over minimally 24 months

This study investigated the safety of administration of long‐acting parenteral testosterone undecanoate (TU) to 122 hypogonadal, mainly elderly men, aged 59.6u2003±u20038.0u2003years (range 18–83u2003years old), with baseline testosterone levels between 5.8 and 12.1u2003nmolu2003l‐1 (meanu2003±u2003SDu2003=u20039.3u2003±u20031.7). Patients were followed for 24u2003months. Plasma testosterone rose from 9.3u2003±u20031.7 to 14.9u2003±u20034.5u2003nmolu2003l‐1 (Pu2003<u20030.01) at 3u2003months, then stabilised at 19.2u2003±u20034.6u2003nmolu2003l‐1 after 6u2003months. International Prostate Symptoms Scores and Residual Bladder Volumes decreased significantly (Pu2003<u20030.01) over the study period. Prostate volume and prostate‐specific antigen levels fluctuated over the study period but had not increased significantly after 24u2003month. Haemoglobin concentrations increased significantly (Pu2003<u20030.001) over the 24u2003months while the haematocrit increased significantly (Pu2003<u20030.001) during the first 15u2003months and then levelled off. Statistical analysis with expressing values as meansu2003±u2003SD masks excesses above reference values of individual patients. These excesses were noted in low numbers, were permanently present in some but not in other individuals, and did not increase in number over the 24u2003month study period. Over 24u2003months treatment with TU appeared acceptably safe, but longer and larger scale studies are needed.