Diagnosing and treating testosterone deficiency in different parts of the world: changes between 2006 and 2010

Aim: An analysis of variations in diagnosing and treating testosterone (T) deficiency between different regions of the world in 2006 was repeated in 2010. Methods: Physicians were interviewed in Germany, Spain, the United Kingdom, Brazil and Saudi Arabia about (1) reasons to use/not to use T. (2) safety (prostate pathology) and other concerns in the decision not to provide T treatment. (3) the actual usage of T preparations for treatment of erectile dysfunction (ED). Results: More men were treated with T in 2010. ED and lack of libido (2006) but also depression and obesity (2010) were regarded as symptoms of T deficiency. For 70% of physicians, severity of complaints was more significant than the laboratory value of T to prescribe T, more so in Germany (96%) than in Spain and Saudi Arabia. Concerns about prostate disease remained strong and, therefore, 11% of eligible patients did not receive T. PDE-5 inhibitors are more often combined with T in 2010 for ED. Conclusion: More appropriate studies and more education of physicians are needed on diagnosing T deficiency, on the role of T in ED and on the evidence-based relative safety of T treatment.     

Performance of Massachusetts Male Aging Study (MMAS) and androgen deficiency in the aging male (ADAM) questionnaires in the prediction of free testosterone in patients aged 40 years or older treated in outpatient regimen

Abstract

Objective: At present, calculated free testosterone assessment is considered as the gold standard in diagnosing male hypogonadism. However, this assessment is not available for all the individuals diagnosed with decreased testicular function. The investigators of this study were, thus, prompted to evaluate whether the androgen deficiency in the aging male (ADAM) and the Massachusetts Male Ageing Study (MMAS) questionnaires could be used to replace biochemical parameters in the diagnosis for hypogonadism in men aged 40 years and above.

Methods: We evaluated 460 men, aged 40 years and above, all volunteers of a screening program for prostate cancer based at the Hospital de Clínicas of Porto Alegre. In this study, we assessed the efficiency of the ADAM and MMAS questionnaires in diagnosing Brazilian men with low levels of total, calculated free and bioavailable testosterone.

Results: The sensitivity of the ADAM questionnaire in diagnosing the calculated free testosterone was 73.6%, whereas specificity was 31.9%. ADAM could be used to properly classify our cohort into normal or hypogonadal individuals in 52.75% of the cases. The sensitivity of the MMAS questionnaire was 59.9%, whereas the specificity was 42.9%, resulting in a successful classification of 51.4% of the patients.

Conclusion: The ADAM and MMAS questionnaires showed adequate sensitivity in diagnosing male patients with low levels of free testosterone. However, because of the lack of specificity, these tools cannot replace calculated free testosterone assessments in men aged 40 years and above.     

Transversal European survey on testosterone deficiency diagnosis

Background: Despite being one of the relevant public health threats among ageing men, testosterone deficiency syndrome (TDS) is under-recognized and under-diagnosed. Objective: To assess current clinical practices of European physicians regarding diagnosis and management of TDS compared with current guidelines. Methods: Postal survey conducted June–November 2008 in France, Germany, Italy and Spain among urologists, endocrinologists and general practitioners to collect information regarding knowledge of TDS. Results: Among 801 respondents, the majority of endocrinologists and urologists had received training on TDS, either initially or as part of continuous medical education. TDS was recognized by 86.5% of physicians as a true clinical entity, and estimated the prevalence at 10–15% of the male population; 73.5% considered that symptoms and a low level of testosterone were required for diagnosis. Treatment preferences were quarterly intramuscular injections (26.3% of physicians), percutaneous gels (23.9%), matrix patch (21.2%), semi-monthly injections (15.4%) and oral therapy (13.4%). Adverse effects of testosterone replacement therapy, such as benign prostatic hyperplasia and prostate cancer, were a concern for physicians. Conclusions: TDS management appeared to be close to that recommended in international guidelines. Signs and symptoms of testosterone deficiency were fairly well known, but some diagnostic and treatment variations were observed.     

Effects of long-term testosterone replacement therapy,with a temporary intermission,on glycemic control of nine hypogonadal men with type 1 diabetes mellitus – a series of case reports

Abstract

Type 2 diabetes mellitus (T2DM) is often associated with obesity and subnormal serum testosterone (T) levels. Until 5 years ago there was no indication that men with type 1 diabetes mellitus (T1DM) had subnormal serum T. But recent studies indicate that about 10% of men with T1DM suffer from hypogonadism, as a rule aged men and men with obesity. While hypogonadal men with T2DM benefit from normalization of their serum T, this has not been investigated in men with T1DM. Nine men with T1DM, erectile dysfunction and hypogonadism (total testosterone?≤?12?nmol/L) received testosterone replacement therapy (TRT). In seven men TRT was intermitted: one man with prostate malignancy and six men because of problems of reimbursement. Incidentally, this provided an opportunity to monitor the effects of withdrawal and of the reinstatement of TRT. In all men, glycemic control (serum glucose and HbA_1c), weight, waist circumference, lipid profiles and erectile function improved upon TRT. The seven men whose TRT was intermitted showed a deterioration which improved again upon reinstatement of TRT. The data suggest that aging and obese men with T1DM might have subnormal T levels and that their glycemic control, lipid profiles and erectile function might benefit from TRT.     

Testosterone and erectile physiology

The role of testosterone deficiency in sexual dysfunction is an important aspect of aging, because it affects such a large proportion of men over 50 years old. A number of age-related factors can cause sexual dysfunction (in particular erectile dysfunction) and testosterone deficiency, such as chronic illness and multiple medications, and the causative link between hypogonadism and erectile dysfunction is still debated. However, studies in castrated animals have proven that addition of testosterone, and its conversion to dihydrotestosterone, can restore erectile function. It appears that testosterone achieves this by peripheral mechanisms (endothelial dependent and independent) and central mechanisms. Testosterone replacement therapy is therefore effective for erectile dysfunction in men with hypogonadism, with success rates of 35–40%. Testosterone supplementation is also important in men who fail on phosphodiesterase type-5 inhibitors, because a minimum plasma concentration of testosterone is required for the successful restoration of erectile function with these agents. Testosterone gels are now the preferred formulation for testosterone supplementation and they can be highly beneficial in a proportion of men with erectile dysfunction.     

Effects of tadalafil treatment combined with physical activity in patients with low onset hypogonadism: results from a not-randomized single arm phase 2 study

Purpose: To investigate a possible relation between penile Doppler ultrasound examination (PDUE) parameters and efficacy of chronic therapy with tadalafil (TAD) combined with a protocol of aerobic physical activity (PA) in patients with late onset hypogonadism (LOH). Methods: The study evaluated 30 patients consecutively enrolled with LOH and erectile dysfunction which present contraindication to hormonal replacement therapy for concomitant prostate disease. These patients were subjected to a combined protocol with phosphodiesterase V selective inhibitors (TAD 5?mg daily) and aerobic PA.

Results: After three months, we observed significant improvements in erectile function [IIEF-5, median (IQR)?=?13.0 (7.0–18.0) versus 6.0 (5.0–6.75); p?p?Conclusion: PA in association with phosphodiesterase V inhibitors could compensate the effects of hypogonadism on erectile function and facilitate the clinical response to these drugs even in the absence of adequate serum concentrations of total testosterone.     

RigiScan data under long-term testosterone therapy: improving long-term blood circulation of penile arteries,penile length and girth,erectile function,and nocturnal penile tumescence and duration

Background: Late-onset hypogonadism (LOH) presents with low serum testosterone (TT) levels and sexual and nonsexual symptoms. Erectile dysfunction affects a man’s self-esteem and as a result partner relationship and quality of life.

Objectives: To investigate the andrological clinical profile outcomes of testosterone therapy (TTh) in men (n?=?88) with symptomatic LOH complaints and symptoms.

Main outcome measures: Erectile function was assessed using the International Index of Erectile Function-5 questionnaire at baseline and at 6 and 12 months of TTh. In addition, penile length was measured at baseline and 12 months. We also evaluated nocturnal penile tumescence (NPT, using RigiScan) and blood flow of cavernous arteries (penile Doppler ultrasonography) at baseline and 12 months of TT.

Materials and methods: Eighty-eight LOH men (M_age 51.1 years) with erectile dysfunction, all with serum TT?<10.4?nmol/L before TTh. Patients received intramuscular long-acting testosterone undecanoate for 12 months.

Results: Following TTh, in all patients, serum TT levels were restored within 3 months to normal levels. Compared with baseline values, erectile function significantly improved at 6 (mean score increase 1.95) and 12 months (mean score increase 2.16). No significant changes in penile length were observed. NPT significantly improved at 12 months in terms of both the frequency (mean increase 1.27 times) and duration of rigidity (mean increase 5.12?min). As regards the blood flow of the cavernous arteries, we observed a significant improvement (decrease of 1.16?cm/s) and end diastolic velocity of the penile arteries.

Conclusion: TTh in men with LOH resulted in improvement of the erectile function, NPT, and to some extent the blood flow of the cavernous arteries.     

Pituitary radiographic abnormalities and clinical correlates of hypogonadism in elderly males presenting with erectile dysfunction

The prevalence of erectile dysfunction rises rapidly with age and is a frequent complaint presented in clinical practice. Although the etiology of erectile dysfunction is multifactorial, 10-20% of evaluations demonstrate testosterone deficiency. Testosterone deficiency due to secondary hypogonadism increases with age. Despite a higher prevalence of secondary hypogonadism in the elderly, there are no studies addressing hypothalamic-pituitary structural abnormalities in elderly impotent men with testosterone deficiency. We retrospectively reviewed the records of all elderly men who presented for general outpatient evaluation of erectile dysfunction from 1996 to 1999. To obtain a cohort control population, the records of 300 patients without erectile dysfunction were also reviewed. Amongst the erectile dysfunction patients, 225 were found to be testosterone deficient (testosterone < 300 ng/dl). Of these patients, 29 were additionally diagnosed with secondary hypogonadism based on a luteinizing hormone (LH) < 13 mIU/ml. Magnetic resonance imaging (MRI) or computed tomography (CT) imaging was available and reviewed in all patients diagnosed with secondary hypogonadism. Ten per cent of these patients had hypothalamic-pituitary imaging abnormalities. The prevalence of pituitary tumors within our population was not significantly elevated compared to the previous general population studies. Small-vessel white matter disease, hyperlipidemia and history of compression fractures were significantly increased in both univariate and multivariate analysis in the erectile dysfunction group compared with the control cohort. This study does not suggest that the use of hypothalamic-pituitary imaging in the evaluation of impotence in elderly men, in the absence of clinical characteristics of other hormonal loss or sella compression symptoms, will increase diagnosis of structural hypothalamic-pituitary abnormalities over that of the general population. However, the yield may increase with very low testosterone levels. These data suggest that there is an increase in ischemic white matter disease in elderly men with hypogonadism that may reflect microvascular injury to the hypothalamic-pituitary. Furthermore, these data confirm that low testosterone is associated with hyperlipidemia in the elderly. Future studies are required to assess the role of hypogonadism and hyperlipidemia, and to determine if treatment of the hormone deficiency improves the lipid profile.     

Time for international action on treating testosterone deficiency syndrome

Aim. Testosterone deficiency is having an increasing impact on men's health because of global aging, higher levels of obesity, diabetes and metabolic syndrome and adverse environmental factors such as stress xenoestrogens and anti-androgens. The question addressed is to what extent the large body of evidence on the benefits and safety of testosterone therapy is applied in clinical practice.

Methods. Demographic data for men over the age of 50 from different regions of the world have been compared with the number of men in that age group estimated from sales figures to be receiving testosterone treatment.

Results. On the basis of estimate that 20% of men over 50 in the general population of each region could be expected to have testosterone deficiency symptoms, on average only these men (0.69%) in most European countries were receiving treatment. Proportion was higher in the UK (1.00%) and Germany (1.89%), but lower in France (0.49%), Italy (0.51%) and Russia (0.54%). Interestingly, Australia had higher figures (1.64%), in spite of tight state control measures on androgen use. The USA has the highest treatment rate (7.96%) and this is increasing rapidly.

If the basis for the diagnosis was the more conventional combination of symptoms plus biochemical evidence of low total and free testosterone levels, androgen deficiency would be expected in at least 5% of men over 50, and percentage treatment rates therefore four times higher. However, even on that basis, only in the USA do these exceed 10%.

Conclusions. International action is urgently needed to raise awareness in the medical profession in the various countries of these remarkably low levels of testosterone treatment. Improvement in this requires education and motivation of doctors and those regulating the healthcare systems. A public awareness campaign is needed to educate men about the symptoms of testosterone deficiency and its impact on their health.     

How to help the aging male? Current approaches to hypogonadism in primary care

Hypogonadism is a common condition which occurs more frequently in older men. It is characterized by low testosterone (T) and is associated with symptoms which are often nonspecific. A key symptom is low libido, but it can also be associated with erectile dysfunction, reduced muscle mass and strength, increased body fat, reduced bone mineral density and osteoporosis, reduced vitality, and depressed mood. Hypogonadism is linked with a variety of comorbid conditions including erectile dysfunction, metabolic syndrome, diabetes, obesity, and osteoporosis. However, the condition is often underdiagnosed. T supplementation in hypogonadism is associated with a range of benefits including improved sexual function, increased lean body mass and/or reduced fat mass, and improved bone mineral density. A variety of T supplementation formulations are available. Although there is no evidence of increased risk of initiating prostate cancer with T supplementation, it is contraindicated in men with prostate cancer. It is important that primary care physicians are aware of both the signs and symptoms of hypogonadism, the monitoring and testing that is required and the merits and advantages of the various T preparations to ensure optimal management of the condition with a treatment approach that best suits patients’ needs.     

The effect of testosterone therapy on lower urinary tract symptoms/bladder and sexual functions in men with symptomatic late-onset hypogonadism

Objective.?To prospectively investigate the effect of testosterone therapy on lower urinary tract symptoms (LUTS)/bladder and sexual functions in men with symptomatic late-onset hypogonadism (SLOH).

Methods.?The study included 25 men (age range 38 to 73 years) presented with sexual dysfunction, having SLOH, at a single university hospital. All men received testosterone replacement therapy with transdermal testosterone 50–100 mg gel per day for one year. Urodynamic studies with pressure-flow analysis, measurement of prostate volume, prostate specific antigen (PSA) and free PSA level, International Prostate Symptom Score (IPSS), Aging Male Symptom (AMS) scale and International Index of Erectile Function (IIEF-5) score were recorded in all men before and after one year of the treatment.

Results.?The mean AMS score significantly decreased from 40.4 ± 7.3 to 28.8 ± 5.31 (p = 0.001), and mean IIEF-5 score significantly increased from 8.84 ± 3.76 to 14.36 ± 3.62 (p = 0.001). The mean maximal bladder capacity and compliance significantly increased (p = 0.007 and p = 0.032, respectively), and mean detrusor pressure at Qmax significantly decreased from pre-treatment to post-treatment (p = 0.017).

Conclusion.?This study suggests that in addition to improvement in sexual functions, testosterone therapy may also improve LUTS/bladder functions by increasing bladder capacity and compliance and decreasing detrusor pressure at maximal flow in men with SLOH.     

The effect of testosterone treatment on prostate histology and apoptosis in men with late-onset hypogonadism

Objectives: To investigate the effect of testosterone replacement therapy (TRT) on prostate histology and apoptosis in men with late-onset hypogonadism (LOH).

Methods: The study included 25 men, having LOH with prostate-specific antigen (PSA) level of 4?ng/ml or less. All patients underwent transrectal ultrasound guided prostate biopsy at baseline, and received testosterone undecanoate treatment for 1 year. Prostate biopsy was repeated at the end of 1 year of testosterone therapy. In addition to clinical and biochemical parameters, prostate histology and apoptotic index (AI) were compared before and after the TRT.

Results: The mean serum total testosterone significantly increased from 178.04?±?51.92 to 496.28?±?103.73?ng/dl (p?=?0.001). No significant differences were observed in serum total and free PSA level, prostate volume and maximal urinary flow rate. There were also no significant differences in AI, stroma/epithelial cells ratio, Ki-67 positive cells and atrophy score of prostate tissue before and after the TRT.

Conclusions: This study demonstrated that TRT did not affect serum PSA level, prostate volume and maximal urinary flow rate. This study also suggests that TRT does not cause the risk for prostate cancer development, because of no significant differences in prostate histology after TRT.     

Decline of serum levels of free testosterone in aging healthy Chinese men

Objective.?To investigate the age-related change of serum androgen levels in healthy men and to define a cut-off value of serum testosterone for the diagnosis of androgen deficiency in the aging male.

Method.?1080 healthy men aged 20 to ?70 years old were enrolled in Beijing, Shanghai, Xian and Chongqing. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T), calculated free testosterone (cFT), sex hormone binding globulin (SHBG), 17beta-oestradiol (E2), the T/LH ratio, and T/SHBG as a free testosterone index (FTI) were all determined.

Results.?Serum total T did not significantly decline, but the cFT, T/LH and FTI progressively decreased with aging. To determine androgen deficiency, the 10th percentile value of men <40 years was defined as the lower cut-off value for cFT, T/LH or FTI, which were 0.3 nmol/L, 2.8 nmol/IU, and 0.4 nmol/IU respectively. With the median value of cFT of men aged between 20 and 49 years as the criterion, the level of cFT was lower in 2.82% of men from 40 to 49 years, in 19.53% from 50 to 59 years, in 22.57% from 60 to 69 years, and in 33.19% of men ?70 years. Taking the above value of cFT as the cut-off point, the prevalence of androgen deficiency in men 40–49 years was 13.0%, 31.8% in men 50–59 years, 30.1% in men 60 to 69 years, and 46.7% in men >70 years.

Conclusions.?(i). While serum total T values do not decline with aging, the levels of cFT gradually decline with aging; (ii) when using the value of cFT of the 10th percentile of men aged 20 to 39 years as the cut-off point, the prevalence of androgen deficiency was <15% before the age of 50 years, and about 30% thereafter, approaching 45% after the age of 70 years; and (iii) in this study the values of T/LH paralleled those of cFT closely; therefore, T/LH could serve as a surrogate for cFT.     

The influence of comorbidities on the aging males’ symptoms scale in patients with erectile dysfunction

Objectives: To investigate if certain common age-related comorbidities are related with a positive aging males’ symptoms (AMS) test outcome.

Methods: This was a multicentric, transversal, observational study carried out in a male population with erectile dysfunction. Comorbidities and testosterone levels were registered. The relationship between comorbidities, testosterone levels, and the AMS test outcomes was studied using the global score and the sub-scale score components.

Results: The study included 1112 patients. In the multivariate analysis the global score strongly correlated with TT?p?Conclusion: Although the AMS test is related to low levels of testosterone, it is also of some limited use for diagnosing hypogonadism because it has low specificity and is influenced by pathologies that are frequent during ageing.     

Effects of testosterone supplementation on prevention of age-related penile remodeling

Abstract

Erectile dysfunction develops among 46.2% of men between 40 and 70 years. Studies demonstrated substitution on detrusor muscle by collagen due testosterone deprivation. It is clear the correlation among aging and oxidative stress, accelerating apoptosis process in many tissues. This study aims to demonstrate the collagen substitution over the muscle fibers on muscle structure of rat’s penis and the effects of testosterone supplementation. Sixteen senescent Wistar rats were divided into two groups: treatment (receiving standard supplementation testosterone dose) and control (receiving equivalent saline solution). Testosterone was dosed on D0 and D56 of study. All penises were prepared with picrosirius colored histology; stereology was applied to determine the volumetric density of collagen fibers (Vv). Analysis of variance demonstrated testosterone group’s replacement therapy to be effective, while the androgenic decline continued by the time of experiment in control group (p?<?0.05). Testosterone group had Vv of 20.6%, lower than control group (47.8%); t-test (p?<?0.001). Pearson’s correlation demonstrated an inverse correlation between the Vv and testosterone’s levels (p?<?0.001). This is a pioneer study on demonstration of structural alterations over the cavernous corpora muscle caused by deprivation of testosterone on elderly rat. These finding implicate that the testosterone levels can influence, not only the libido, but also the erectile function.     

Preventing diseases of the prostate in the elderly using hormones and nutriceuticals

The prostate has only one function, namely to secrete fluid containing substances that are needed for reproduction. This requires an extremely high concentration of androgens in the tissues. Benign prostatic hypertrophy (BPH) seems to be related to the long-term exposure of the prostate to the strong androgen 5α-dihydrotestosterone (DHT) and, possibly, to estrogens. The relation between prostate cancer and androgens is suggested to be U-shaped, with both extremes of androgen concentrations being associated with increased risk of invasive cancer.

In the treatment of patients with BPH, the lipidic liposterolic extracts of Serenoa repens were as effective as the pharmaceutical inhibitors of the 5α-reductase enzyme or α₁-adrenergic blockers in relieving urinary symptoms. In addition to moderately inhibiting the 5α-reductase activity, Serenoa seems to exert anti-inflammatory and complementary cellular actions with beneficial effects on the prostate. Unlike the pharmaceutical 5α-reductase inhibitors, finasteride and dutasteride, Serenoa does not suppress serum PSA, facilitating the follow-up and the early detection of prostate cancer.

We suggest a strategy to prevent prostate cancer that aims at providing men with partial androgen deficiency correct testosterone substitution with a sustained release buccal bio-adhesive tablet. In addition, food supplementation with extracts of Serenoa repens and a combination of the antioxidants selenium, (cis)-lycopene and natural vitamin E, together with fish oil rich in long-chain polyunsaturated essential fatty acids of the omega-3 group seems warranted. Clearly, a holistic approach including careful clinical and biological monitoring of the aging man and his prostate remains mandatory.     

The effect of lifestyle modification and glycemic control on the efficiency of sildenafil citrate in patients with erectile dysfunction due to type-2 diabetes mellitus

Abstract

Objectives: We evaluated the effect of lifestyle modifications and glycemic control on the efficiency of sildenafil citrate in patients with type-2 diabetes (T2DM) and erectile dysfunction (ED).

Methods: Eighty-three men with ED due to T2DM were included in the study. The Group 1 (n?=?41) patients received lifestyle modifications (diet and exercise), and medical treatment for intensive glycemic control. In Group 2 (n?=?42), in addition to the intensive glycemic control, the patients were given sildenafil citrate® 100?mg for 2–3 per weeks. The changes in ED were compared between the two groups after three months of treatment.

Results: The mean age was 54.9?±?9.1 (26–75) years. An increase in the IIEF-5 scores was observed in 23 of 41 patients in Group 1 (44.2%) and 29 of 42 in Group 2 (55.8%). When the changes of the IIEF-5 scores were evaluated, the mean increase was 2.5 in Group 1, and 5.0 in Group 2 (p?=?0.012). The mean IIEF changes according to the duration of diabetes were 4.8 in <5 years, 3.6 in 5–10 years and 1.6 in >10 years (p?=?0.021).

Conclusions: Glycemic control and lifestyle changes are not solely adequate for a better sexual function in ED due to diabetes, and sildenafil citrate should be used additionally.     

Testosterone therapy in erectile dysfunction

Studies in animals have indicated that the nitric oxide erectile pathway is testosterone-dependent. Castration induces erectile dysfunction and a reduction in nitric oxide synthase-stained nerves in erectile tissue. Furthermore, castration adversely affects penile hemodynamics and smooth muscle content, leading to veno-occlusive dysfunction. Testosterone replenishment reverses these physiological, biochemical and structural changes. Several clinical studies have demonstrated the benefits of a combination of testosterone and sildenafil. A recently published, multicenter study evaluated the safety and efficacy of testosterone gel 1% (Testogel®; Schering AG, Germany/AndroGel®; Solvay Pharmaceuticals) vs. placebo gel in conjunction with sildenafil, in producing an erectile response in hypogonadal men who did not respond to treatment with sildenafil alone for erectile dysfunction. The selection criteria required subjects to have had erectile dysfunction for at least 3 months, to be non-responsive to 100 mg sildenafil and to have low testosterone levels (&lt;?400 ng/dl). The primary efficacy measurement was the mean change from baseline in the Erectile Function domain of the International Index of Erectile Function (IIEF). Secondary outcome measures included the mean change from baseline in the other domains and the total sum of the IIEF. Subjects were randomized to receive either testosterone gel + sildenafil, or placebo gel + sildenafil for 12 weeks. Testosterone therapy with testosterone gel improved the erectile response to sildenafil. Therefore, testosterone therapy may be considered for the treatment of erectile dysfunction in men with low to low-normal testosterone levels, who have failed prior treatment with sildenafil alone. Consequently, it is important to screen for hypogonadism in men who fail PDE5 inhibitors.