Joanne E. Nettleship

Physiological Testosterone Replacement Therapy Attenuates Fatty Streak Formation and Improves High-Density Lipoprotein Cholesterol in the Tfm Mouse. An Effect That Is Independent of the Classic Androgen Receptor

Background— Research supports a beneficial effect of physiological testosterone on cardiovascular disease. The mechanisms by which testosterone produces these effects have yet to be elucidated. The testicular feminized (Tfm) mouse exhibits a nonfunctional androgen receptor and low circulating testosterone concentrations. We used the Tfm mouse to determine whether testosterone modulates atheroma formation via its classic signaling pathway involving the nuclear androgen receptor, conversion to 17&bgr;-estradiol, or an alternative signaling pathway. Methods and Results— Tfm mice (n=31) and XY littermates (n=8) were separated into 5 experimental groups. Each group received saline (Tfm, n=8; XY littermates, n=8), physiological testosterone alone (Tfm, n=8), physiological testosterone in conjunction with the estrogen receptor &agr; antagonist fulvestrant (Tfm, n=8), or physiological testosterone in conjunction with the aromatase inhibitor anastrazole (Tfm, n=7). All groups were fed a cholesterol-enriched diet for 28 weeks. Serial sections from the aortic root were examined for fatty streak formation. Blood was collected for measurement of total cholesterol, high-density lipoprotein cholesterol (HDLC), non-HDLC, testosterone, and 17&bgr;-estradiol. Physiological testosterone replacement significantly reduced fatty streak formation in Tfm mice compared with placebo-treated controls (0.37±0.07% versus 2.86±0.39%, respectively; P≤0.0001). HDLC concentrations also were significantly raised in Tfm mice receiving physiological testosterone replacement compared with those receiving placebo (2.81±0.30 versus 2.08±0.09 mmol/L, respectively; P=0.05). Cotreatment with either fulvestrant or anastrazole completely abolished the improvement in HDLC. Conclusion— Physiological testosterone replacement inhibited fatty streak formation in the Tfm mouse, an effect that was independent of the androgen receptor. The observed increase in HDLC is consistent with conversion to 17&bgr;-estradiol.

Testosterone and atherosclerosis in aging men: purported association and clinical implications.

Two of the strongest independent risk factors for coronary heart disease (CHD) are increasing age and male sex. Despite a wide variance in CHD mortality between countries, men are consistently twice as likely to die from CHD than their female counterparts. This sex difference has been attributed to a protective effect of female sex hormones, and a deleterious effect of male sex hormones, upon the cardiovascular system. However, little evidence suggests that testosterone exerts cardiovascular harm. In fact, serum levels of testosterone decline with age, and low testosterone is positively associated with other cardiovascular risk factors. Furthermore, testosterone exhibits a number of potential cardioprotective actions. For example, testosterone treatment is reported to reduce serum levels of the pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and to increase levels of the anti-inflammatory cytokine IL-10; to reduce vascular cell adhesion molecule (VCAM)-1 expression in aortic endothelial cells; to promote vascular smooth muscle and endothelial cell proliferation; to induce vasodilatation and to improve vascular reactivity, to reduce serum levels of the pro-thrombotic factors plasminogen activator inhibitor (PAI)-1 and fibrinogen; to reduce low-density lipoprotein-cholesterol (LDL-C); to improve insulin sensitivity; and to reduce body mass index and visceral fat mass. These actions of testosterone may confer cardiovascular benefit since testosterone therapy reduces atheroma formation in cholesterol-fed animal models, and reduces myocardial ischemia in men with CHD. Consequently, an alternative hypothesis is that an age-related decline in testosterone contributes to the atherosclerotic process. This is supported by recent findings, which suggest that as many as one in four men with CHD have serum levels of testosterone within the clinically hypogonadal range. Consequently, restoration of serum levels of testosterone via testosterone replacement therapy could offer cardiovascular, as well as other, clinical advantages to these individuals.

Effects of testosterone replacement therapy withdrawal and re-treatment in hypogonadal elderly men upon obesity, voiding function and prostate safety parameters

Abstract Whether testosterone replacement therapy (TRT) is a lifelong treatment for men with hypogonadism remains unknown. We investigated long-term TRT and TRT withdrawal on obesity and prostate-related parameters. Two hundred and sixty-two hypogonadal patients (mean age 59.5) received testosterone undecanoate in 12-week intervals for a maximum of 11 years. One hundred and forty-seven men had TRT interrupted for a mean of 16.9 months and resumed thereafter (Group A). The remaining 115 patients were treated continuously (Group B). Prostate volume, prostate-specific antigen (PSA), residual voiding volume, bladder wall thickness, C-reactive protein (CRP), aging male symptoms (AMS), International Index of erectile function – erectile function (IIEF-EF) and International Prostate Symptoms Scores (IPSS) were measured over the study period with anthropometric parameters of obesity, including weight, body mass index (BMI) and waist circumference. Prior to interruption, TRT resulted in improvements in residual voiding volume, bladder wall thickness, CRP, AMS, IIEF-EF, IPSS and obesity parameters while PSA and prostate volume increased. TRT interruption reduced total testosterone to hypogonadal levels in Group A and resulted in worsening of obesity parameters, AMS, IPSS, residual voiding volume and bladder wall thickness, IIEF-EF and PSA while CRP and prostate volume were unchanged until treatment resumed whereby these effects were reversed. TRT interruption results in worsening of symptoms. Hypogonadism may require lifelong TRT.

Testosterone suppresses the expression of regulatory enzymes of fatty acid synthesis and protects against hepatic steatosis in cholesterol-fed androgen deficient mice

AIMSnNon-alcoholic fatty liver disease and its precursor hepatic steatosis is common in obesity and type-2 diabetes and is associated with cardiovascular disease (CVD). Men with type-2 diabetes and/or CVD have a high prevalence of testosterone deficiency. Testosterone replacement improves key cardiovascular risk factors. The effects of testosterone on hepatic steatosis are not fully understood.nnnMAIN METHODSnTesticular feminised (Tfm) mice, which have a non-functional androgen receptor (AR) and very low serum testosterone levels, were used to investigate testosterone effects on high-cholesterol diet-induced hepatic steatosis.nnnKEY FINDINGSnHepatic lipid deposition was increased in Tfm mice and orchidectomised wild-type littermates versus intact wild-type littermate controls with normal androgen physiology. Lipid deposition was reduced in Tfm mice receiving testosterone treatment compared to placebo. Oestrogen receptor blockade significantly, but only partially, reduced the beneficial effects of testosterone treatment on hepatic lipid accumulation. Expression of key regulatory enzymes of fatty acid synthesis, acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) were elevated in placebo-treated Tfm mice versus placebo-treated littermates and Tfm mice receiving testosterone treatment. Tfm mice on normal diet had increased lipid accumulation compared to littermates but significantly less than cholesterol-fed Tfm mice and demonstrated increased gene expression of hormone sensitive lipase, stearyl-CoA desaturase-1 and peroxisome proliferator-activated receptor-gamma but FASN and ACACA were not altered.nnnSIGNIFICANCEnAn action of testosterone on hepatic lipid deposition which is independent of the classic AR is implicated. Testosterone may act in part via an effect on the key regulatory lipogenic enzymes to protect against hepatic steatosis.

Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study.

Subnormal levels of testosterone are associated with significant negative health consequences, with higher risks of all‐cause and cardiovascular mortality. The numbers of studies reporting on the benefits of normalisation of testosterone is increasing but longer‐term data on (elderly) men receiving testosterone treatment are almost nonexistent. In this single‐centre, cumulative, prospective, registry study, 115 hypogonadal men (mean age 59.05 years) received injections with testosterone undecanoate in 12‐week intervals for up to 10 years. Waist circumference, body weight and mean BMI dropped progressively with statistical significance versus previous year for 7 years and, respectively, 8 years for weight and body mass index. Similarly, fasting glucose displayed a significant decrease after the first year continuing to decrease thereafter. A decline in HbA1c, from 6.4% to 5.6% (mean <6%), was observed from year 2 on, together with a decrease in the ratio of triglycerides:high‐density lipoprotein (HDL), a surrogate marker of insulin resistance, with an increase in HDL levels. The total cholesterol:HDL ratio and non‐HDL cholesterol declined significantly. A decrease was also observed in systolic and diastolic blood pressure, with a decrease in levels of the inflammation marker C‐reactive protein. No major adverse cardiovascular events were observed throughout the study.

Physiologic Testosterone Therapy has no Effect on Serum Levels of Tumour Necrosis Factor-α in Men with Chronic Heart Failure

Physiological testosterone therapy increases exercise capacity and reduces symptom scores in men with chronic heart failure (CHF). Tumour necrosis factor-alpha (TNF-α) exerts a significant pathologic activity in CHF, and physiologic testosterone replacement therapy is associated with reduced serum levels of TNF-α in hypogonadal men with concomitant coronary artery disease. It is unknown whether testosterone exerts a similar immunomodulatory action in men with CHF. Consequently, serum levels of TNF-α were measured in men with CHF, before and after physiologic testosterone therapy administered in three placebo-controlled studies, for either 6 hours (two 30-mg buccal tablets, n = 12) or 3 months (fortnightly 100 mg intra muscular injection, n = 20; or daily 5 mg transdermally, n = 62). The effects of testosterone were also assessed on lipopolysaccharide (LPS)-induced TNF-α production in whole blood obtained from 27 men with CHF. Incubation with testosterone (10 nM, 1 μM, and 100 μM) resulted in a reduction in LPS-induced TNF-α production from 12.6 ± 1.3 to 11.2 ± 1.1 (P = 0.053), 10.3 ± 1.1 (P = 0.0046), and 9.2 ± 1.1 (P = 0.000066) ng/ml, respectively. However in men with CHF, serum levels of TNF-α were similar before and after treatment with testosterone or placebo, irrespective of the length of study or route of administration. The clinically beneficial actions of testosterone in men with CHF are unlikely to be mediated by reducing TNF-α.

Early weight loss predicts the reduction of obesity in men with erectile dysfunction and hypogonadism undergoing long-term testosterone replacement therapy

Abstract We and others have previously shown that testosterone replacement therapy (TRT) results in sustained weight loss in the majority of middle-aged hypogonadal men. Previously, however, a small proportion failed to lose at least 5% of their baseline weight. The reason for this is not yet understood. In the present study, we sought to identify early indicators that may predict successful long-term weight loss, defined as a reduction of at least 5% of total body weight relative to baseline weight (T0), in men with hypogonadism undergoing TRT. Eight parameters measured were assessed as potential predictors of sustained weight loss: loss of 3% or more of baseline weight after 1 year of TU treatment, severe hypogonadism, BMI, waist circumference, International Prostate Symptom Score (IPSS), glycated hemoglobin (HbA1C), age and use of vardenafil. Among the eight measured parameters, three factors were significantly associated with sustained weight loss over the entire period of TU treatment: (1) a loss of 3% of the baseline body weight after 1 year of TRT; (2) baseline BMI over 30; and (3) a waist circumference >102u2009cm. Age was not a predictor of weight loss.

Is there a relationship between the severity of erectile dysfunction and the comorbidity profile in men with late onset hypogonadism

Abstract Objective: To determine whether the severity of erectile dysfunction (ED) in a man diagnosed with late-onset hypogonadism (LOH) gives information about his metabolic syndrome state, as patients with LOH often have sexual symptoms and associated cardiovascular and metabolic comorbidities, but the role of ED in predicting the prevalence of comorbid disease in men with low levels of testosterone is currently unknown. Patients and methods: Men (130) diagnosed with LOH and fulfilling the criteria of a total testosterone level of <3.5 ng/mL (<12 nmol/L), and with an erectile function domain score of <21 on the International Index of Erectile Function questionnaire (IIEF, questions 1–5), were enrolled for a subsequent trial of supplementation with testosterone undecanoate. Demographic data were recorded at baseline. The men completed three standardised questionnaires to assess sexual health, including the International Prostate Symptom Score, Ageing Males Symptoms (AMS) and IIEF Sexual Health Inventory for Men (SHIM). Patients were stratified by the severity of ED, with SHIM scores of 1–7 considered severe, 8–11 moderate, and 12–16 mild to moderate. Levels of serum testosterone, sex hormone binding globulin (SHBG) and lipids (total cholesterol, triglycerides, high-density and low-density lipoprotein) were assessed, along with plasma fasting glucose and glycated haemoglobin (HbA1c) levels. Body weight, body mass index and waist circumference were also recorded. Results: There was a significant association between the severity of ED and mean weight (P < 0.001), waist circumference (P < 0.001), triglycerides (P = 0.009), total cholesterol (P = 0.027), HbA1c (P < 0.001), fasting glucose (P = 0.003) and AMS scores (P = 0.043). There were no significant differences in testosterone fractions and SHBG levels between the ED subgroups. There was a positive correlation between the prevalence of diabetes mellitus (type 1 and type 2) and the severity of ED in these men (P = 0.018). Conclusions: The descriptive data showed that a greater severity of ED in men with LOH correlated with an increased waist circumference, hyperglycaemia, hypertriglyceridaemia, hyperlipidaemia, and a history of diabetes mellitus. Severe ED is a prognostic indicator of comorbidities in men with LOH.

Waist circumference is superior to weight and BMI in predicting sexual symptoms, voiding symptoms and psychosomatic symptoms in men with hypogonadism and erectile dysfunction

Waist circumference is considered a useful predictor of obesity‐associated cardiovascular risk, but its use as an indicator of sexual health status and quality of life (QoL) in hypogonadal men is unknown. We investigated whether three measurements of obesity, weight, body mass index and waist circumference, correlate with the International Index of Erectile Function‐5 (IIEF‐5), the Aging Males’ Symptoms (AMS) and the International Prostate Symptom Score (IPSS) questionnaires. A total of 261 patients were enrolled in a prospective study on hypogonadism treatment with intramuscular long‐acting testosterone undecanoate. Patients with total testosterone ≤3.5 ng ml−1 were enrolled, and baseline demographic data were recorded. Patients response to IIEF, IPSS and AMS standardised questionnaires was recorded to evaluate health‐related QoL. The mean length of treatment and follow‐up was 4.7 years (max 6 years). ANOVA regression analysis showed that waist circumference was significantly inversely proportional to IIEF‐5 and directly proportional to AMS and IPSS. Weight was inversely proportional to IIEF and directly proportional to IPSS but not associated with AMS. BMI had no proportionality to measurements of sexual function and quality of life. These results suggest that among weight, BMI and waist circumference, the latter is the best predictor of health‐related QoL in men with hypogonadism.

Testosterone replacement therapy improves the health-related quality of life of men diagnosed with late-onset hypogonadism

Abstract Objectives: To test the hypothesis that testosterone replacement therapy (TRT) improves the long-term health-related quality of life (HRQoL) of men with late-onset hypogonadism (LOH), as studies have shown that sub-physiological testosterone levels have a negative impact on psychological (e.g. mood, vitality, libido and sexual interest) and physical features (e.g. erectile function and physical strength), all of which contribute to a sense of well-being. Patients and methods: In all, 261 patients (mean age 58 years) diagnosed with LOH were treated with long-acting intramuscular testosterone undecanoate (TU) for up to 5 years. Health quality indicators including the International Prostate Symptom Score (IPSS), the five-item version of the International Index of Erectile Function (IIEF-5), the Aging Males’ Symptoms (AMS) scale, and the percentage of patients reporting joint and muscle pain were measured at baseline and at each visit. The means were then plotted over time in parallel with mean total testosterone (TT) levels. Results: Both the mean IPSS and AMS scores fell significantly within the first 3 months and the mean IIEF-5 score and TT levels increased within the first 3 months. All four parameters continued to improve over the course of the trial. The percentage of patients reporting both joint and muscle pain decreased during TRT. Conclusions: This prospective, observational and longitudinal analysis shows a clear improvement in both psychological and physical characteristics as physiological testosterone levels are reached and maintained contributing to an improvement in the HRQoL in men with diagnosed LOH.