ArticleLiterature Review

Síndrome de déficit de testosterona: diagnóstico y tratamiento

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Abstract

Resumen El síndrome de déficit de testosterona (SDT) es una entidad clínica y bioquímica muy común, que afecta aproximadamente al 2-5% de los varones a partir de los 40 años. Desde un punto de vista clínico asocia más comúnmente disminución del deseo y actividad sexual, disfunción eréctil, disminución de la energía y cambios en el estado de ánimo, junto con unos niveles de testosterona (T) < 8-12 nmol/l. Los cuestionarios no son de utilidad en el screening, pero pueden serlo en el diagnóstico y en el seguimiento. Para el diagnóstico es necesario que existan preferiblemente múltiples síntomas de hipogonadismo junto con 2 determinaciones matutinas de T por debajo del límite de normalidad de referencia del laboratorio. La determinación de la LH y la SHBG puede ayudarnos en el diagnóstico a la hora de determinar la causa y el nivel de T libre, respectivamente. Las contraindicaciones para el tratamiento son el cáncer de próstata activo, la insuficiencia cardiaca grado IV, el cáncer de mama, el deseo genésico y la presencia de hematocrito > 54%. El tratamiento se basa en la modificación de la causa del SDT, si existe, junto con la suplementación de T. El objetivo es conseguir niveles de T en el rango medio fisiológico de normalidad. El seguimiento se realiza mediante historia clínica, analítica (PSA, T + SHBG, hematocrito, glucosa y perfil lípídico) y tacto rectal, a los 3, 6 y 12 meses de iniciar el tratamiento.

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Importance Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions. Objective To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). Design, Setting, and Participants The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014. Interventions Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. Main Outcomes and Measures The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to −26), executive function (Trail-Making Test B minus A; range, −290 to 290), and spatial ability (Card Rotation Test; score range, −80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. Results Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (−0.28 [95% CI, −0.76 to 0.19]; P = .24), executive function (−5.51 [95% CI, −12.91 to 1.88]; P = .14), or spatial ability (−0.12 [95% CI, −1.89 to 1.65]; P = .89). Conclusions and Relevance Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions. Trial Registration clinicaltrials.gov Identifier: NCT00799617
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Introduction: Testosterone deficiency (TD), also known as hypogonadism, is a condition affecting a substantial proportion of men as they age. The diagnosis and management of TD can be challenging and clinicians should be aware of the current literature on this condition. Aim: To review the available literature concerning the diagnosis and management of TD and to provide clinically relevant recommendations from the Fourth International Consultation for Sexual Medicine (ICSM) meeting. Methods: A literature search was performed using the PubMed database for English-language original and review articles published or e-published up to January 2016. Main outcome measures: Levels of evidence (LoEs) and grades of recommendations are provided based on a thorough analysis of the literature and committee consensus. Results: Recommendations were given for 12 categories of TD: definition, clinical diagnosis, routine measurement, screening questionnaires, laboratory diagnosis, threshold levels for the biochemical diagnosis of TD, prostate cancer, cardiovascular disease, fertility, testosterone (T) formulations, alternatives to T therapy, and adverse events and monitoring. A total of 42 recommendations were made: of these, 16 were unchanged from the Third ICSM and 26 new recommendations were made during this Fourth ICSM. Most of these recommendations were supported by LoEs 2 and 3. Several key new recommendations include the following: (i) the clinical manifestations of TD occur as a result of decreased serum androgen concentrations or activity, regardless of whether there is an identified underlying etiology [LoE = 1, Grade = A]; (ii) symptomatic men with total T levels lower than 12 nmol/L or 350 ng/dL should be treated with T therapy [LoE = 1, Grade = C]; (iii) a trial of T therapy in symptomatic men with total T levels higher than 12 nmol/L or 350 ng/dL can be considered based on clinical presentation [LoE = 3, Grade = C]; (iv) there is no compelling evidence that T treatment increases the risk of developing prostate cancer or that its use is associated with prostate cancer progression [LoE = 1, Grade = C]; and (v) the weight of evidence indicates that T therapy is not associated with increased cardiovascular risk [LoE = 2, Grade = B]. Conclusion: TD is an important condition that can profoundly affect the sexual health of men. We provide guidance regarding its diagnosis and management. Men with TD who receive treatment often experience resolution or improvement in their sexual symptoms and non-sexual health benefits.
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Introduction: Controversy exists as to whether erectile response to phosphodiesterase type 5 inhibitors is compromised in men with low total testosterone (TT) levels. This is amplified by reports of improved response to phosphodiesterase type 5 inhibitor therapy after coadministration of testosterone replacement therapy in hypogonadal men unresponsive to phosphodiesterase type 5 inhibitors. Aim: To determine whether TT and luteinizing hormone levels influence efficacy of tadalafil for erectile dysfunction in men with concomitant lower urinary tract symptoms and benign prostatic hyperplasia. Methods: This integrated analysis included 1,075 men randomized to once-daily tadalafil 5 mg (n = 540) or placebo (n = 535) for 12 weeks in three prospective clinical trials who had not received concomitant testosterone replacement therapy. Subjects were categorized at baseline by low vs normal TT levels (n = 1,049; <300 vs ≥300 ng/dL) and normal vs high luteinizing hormone levels (n = 1,058; ≤9.4 vs >9.4 mIU/mL). Treatment-group differences in International Index of Erectile Function (IIEF) by hormone subgroups were assessed using analysis of covariance. Main outcome measures: Changes in IIEF erectile function domain and other domain scores. Results: The overall study population was comprised primarily of white men (>86%) with a mean age range of 64 to 70 years. Median baseline TT level in the integrated population was 355 ng/dL; levels were lower than 300 ng/dL (cutoff for normal) in 32.4% of men. Men with low TT levels reported diabetes (21.8%), cardiovascular disease (54.1%), and hypertension (49.1%) numerically more often than men with normal TT levels (10.6%, 43.2%, and 36.7%, respectively). Low TT and high luteinizing hormone levels were associated with numerically, but not statistically significantly, lower 12-week IIEF domain scores compared with those with normal levels. Changes in most 12-week IIEF domain scores showed that tadalafil was significantly more effective than placebo (P < .02). Conclusion: Low TT levels at baseline did not negatively influence response to tadalafil in men of advancing age with concomitant lower urinary tract symptoms and benign prostatic hyperplasia and erectile dysfunction.
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Male hypogonadism is often associated with impaired fertility. In special cases, treatment with gonadotropins can induce, maintain or augment spermatogenesis. Patients responsive to such regimens are men with secondary hypogonadism, lacking gonadotropin secretion due to pituitary disorders or hypothalamic insufficiency. Such diseases may be inherited or acquired. Available substances are recombinant follicle-stimulating hormone and human chorionic gonadotropin (substituting activity of luteinizing hormone). Recommendation based on current research is that treatment should last at least 2 years. Successful induction of spermatogenesis is more likely in men with pituitary disorders than in those lacking hypothalamic GnRH secretion (e.g. patients with Kallman Syndrome).
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Obesity has reached global epidemic proportions and is associated with multiple comorbidities, including cardiovascular disease. A novel predictor of cardiovascular disease is elevated central systolic blood pressure. In fact, lifestyle modifications have been shown to decrease the central systolic blood pressure in overweight and obese men. The mechanism underlying these changes has yet to be fully elucidated. Interestingly, testosterone has been found to have cardioprotective effects. Moreover, serum testosterone levels are lower in obese men than in normal weight men. However, it is still unclear whether testosterone participates in the decrease of central blood pressure in overweight and obese men following lifestyle modifications. So, the purpose of the present study was to investigate the effect of testosterone on central systolic blood pressure in overweight and obese men before and after the 12-week lifestyle modification program. Forty-four overweight and obese men completed a 12-week lifestyle modification program (aerobic exercise training and dietary modifications). For all participants, central systolic blood pressure and serum testosterone levels were measured before and after the program. After the program, central systolic blood pressure was significantly decreased while serum total testosterone levels were significantly increased in overweight and obese men. Moreover, we also found a significant negative relationship between the change in serum testosterone levels and that in central systolic blood pressure. The present study suggests that increased serum testosterone levels likely contribute to a decrease in central blood pressure in overweight and obese men.
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Context: Testosterone (T) levels decline with age and lower T has been associated with increased mortality in aging men. However, the associations of its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with mortality are poorly defined. Objective: We assessed associations of T, DHT, and E2 with all-cause and ischemic heart disease (IHD) mortality in older men. Participants: Participants were community-dwelling men aged 70 to 89 years who were residing in Perth, Western Australia. Main outcome measures: Plasma total T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning samples collected in 2001 to 2004 from 3690 men. Deaths to December 2010 were ascertained by data linkage. Results: There were 974 deaths (26.4%), including 325 of IHD. Men who died had lower baseline T (12.8±5.1 vs 13.2±4.8 nmol/L [mean±SD], P=.013), DHT (1.4±0.7 vs 1.5±0.7 nmol/L, P=.002), and E2 (71.6±29.3 vs 74.0±29.0 pmol/L, P=.022). After allowance for other risk factors, T and DHT were associated with all-cause mortality (T: quartile [Q] Q2:Q1, adjusted hazard ratio [HR]=0.82, P=.033; Q3:Q1, HR=0.78, P=.010; Q4:Q1, HR=0.86, P>.05; DHT: Q3:Q1, HR=0.76, P=.003; Q4:Q1, HR=0.84, P>.05). Higher DHT was associated with lower IHD mortality (Q3:Q1, HR=0.58, P=.002; Q4:Q1, HR=0.69, P=.026). E2 was not associated with either all-cause or IHD mortality. Conclusions: Optimal androgen levels are a biomarker for survival because older men with midrange levels of T and DHT had the lowest death rates from any cause, whereas those with higher DHT had lower IHD mortality. Further investigations of the biological basis for these associations including randomized trials of T supplementation are needed.
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Androgen-deficient men are at increased risk of osteoporosis. The extent to which testosterone can prevent and treat osteoporosis in men remains unclear. We performed a systematic review and meta-analysis of randomized placebo-controlled trials in men to estimate the effect of testosterone use on bone health outcomes. The review encompassed librarian-designed search strategies using MEDLINE (1966 to March 2005), EMBASE (1988 to March 2005), and Cochrane CENTRAL (inception to March 2005); a review of reference lists from included studies; and content expert files. Independently and in duplicate, we assessed the methodological quality of the eligible trials and collected data on bone mineral density and bone fractures at the longest point of complete follow-up. We included eight trials enrolling 365 patients. Two trials followed patients for more than 1 yr. Meta-analysis of these trials showed that, compared with placebo, im testosterone was associated with an 8% (95% confidence interval, 4%, 13%) gain in lumbar bone mineral density and transdermal testosterone had no significant impact. Testosterone use was associated with a nonsignificant 4% (95% confidence interval, -2%, 9%) gain in femoral neck bone mineral density with unexplained differences in results across trials (26% of these differences were not explained by chance alone). No trials measured or reported the effect of testosterone on fractures. Intramuscular testosterone moderately increased lumbar bone density in men; the results on femoral neck bone density are inconclusive. Without bone fracture data, the available trials offer weak and indirect inferences about the clinical efficacy of testosterone on osteoporosis prevention and treatment in men.
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Context: Obesity in men is associated with low serum testosterone and both are associated with several diseases and increased mortality. Objectives: Examine the direction and causality of the relationship between body mass index (BMI) and serum testosterone. Design: Bi-directional Mendelian randomization (MR) analysis on prospective cohorts. Setting: Five cohorts from Denmark, Germany and Sweden (Inter99, SHIP, SHIP Trend, GOOD and MrOS Sweden). Participants: 7446 Caucasian men, genotyped for 97 BMI-associated SNPs and three testosterone-associated SNPs. Main outcome measures: BMI and serum testosterone adjusted for age, smoking, time of blood sampling and site. Results: 1 SD genetically instrumented increase in BMI was associated with a 0.25 SD decrease in serum testosterone (IV ratio: -0.25, 95% CI: -0.42--0.09, p = 2.8*10-3). For a body weight reduction altering the BMI from 30 to 25 kg/m2, the effect would equal a 13% increase in serum testosterone. No association was seen for genetically instrumented testosterone with BMI, a finding that was confirmed using large-scale data from the GIANT consortium (n = 104349). Conclusions: Our results suggest that there is a causal effect of BMI on serum testosterone in men. Population level interventions to reduce BMI are expected to increase serum testosterone in men.
Article
Context The interpretation of available clinical evidence related to the effect of testosterone (T) treatment (TTh) on sexual function has been inconsistent, in part due to the use of different and self-reported measures to assess outcomes. The International Index of Erectile Function (IIEF) is the most frequently used validated tool to assess male sexual function. Objective To perform a meta-analysis of available data evaluating the effect of TTh on male sexual function using IIEF as the primary outcome. Evidence acquisition An extensive Medline, Embase, and Cochrane search was performed including all placebo-controlled randomized clinical trials enrolling men comparing the effect of TTh on sexual function. Evidence synthesis Out of 137 retrieved articles, 14 were included in the study enrolling 2298 participants, with a mean follow-up of 40.1 wk and mean age of 60.2 ± 6.5 yr. Using IIEF-erectile function domain (IIEF-EFD) as the outcome, we found that TTh significantly improved erectile function compared with placebo (mean difference = 2.31 [1.41;3.22] IIEF-EFD score, p < 0.0001). Patients with more severe hypogonadism (total T < 8 nmol/l) reported greater changes in final IIEF-EFD score when compared with those with a milder T deficiency (total T < 12 nmol/l; 1.47 [0.90;2.03] and 2.95 [1.86;4.03] for total T < 12 nmol/l and <8 nmol/l, respectively, Q = 5.61, p = 0.02). The magnitude of the effect was lower in the presence of metabolic derangements, such as diabetes and obesity. Other aspects of sexual function, as evaluated by IIEF subdomains, were also improved with TTh including libido, intercourse satisfaction, orgasm, and overall sexual satisfaction. Conclusions TTh significantly improves erectile function and other sexual parameters as measured by IIEF in hypogonadal men. These results argue that sexual dysfunction should be considered a hallmark manifestation of T deficiency, since those symptoms can be significantly improved with normalization of serum T. In addition, these results suggest that TTh alone may be considered a reasonable treatment for hypogonadal men with milder degrees of erectile dysfunction, whereas the addition of other treatments, such as phosphodiesterase type 5 inhibitors, may be more appropriate for men with more severe erectile dysfunction. Patient summary We investigated the effect of testosterone treatment on sexual function by performing a meta-analysis of all available studies that used the most frequently used assessment tool, the International Index of Erectile Function. We found that testosterone treatment significantly improves erectile dysfunction, as well as other aspects of sexual function, in men with testosterone deficiency. This treatment may be all that is required for hypogonadal men with milder erectile dysfunction; however, additional treatments may be necessary in more severe cases.
Article
Context: Concern exists that testosterone replacement therapy (TRT) might increase the risk of prostate disease. There is limited data regarding the impact of TRT on prostate androgen concentrations. Objective: Determine the dose-dependent effects of exogenous testosterone (T) administration on intraprostatic androgen concentrations. Design: 12-week, double-blinded, randomized, placebo-controlled trial. Setting: Academic medical center Participants: 62 healthy eugonadal men, aged 25-55 years. Interventions: Subjects were randomly assigned to receive injections of acyline, a GnRH antagonist (to achieve medical castration) every 2 weeks, plus transdermal T gel (1.25g, 2.5g, 5.0g, 10g or 15g daily), or placebo injections and transdermal gel for 12 weeks. Main outcomes: Serum T and DHT were measured at baseline and every 2 weeks during treatment. Intraprostatic T and DHT concentrations were assessed from tissue obtained through ultrasound-guided prostate needle biopsies at week 12. Androgens were quantified by LC-MS/MS. Results: 51 men completed the study and were included in analysis. There were no significant adverse events. Exogenous T resulted in dose-dependent increase in serum T and DHT concentrations (190-770 and 60-180 ng/dL, respectively). While intraprostatic T differed among dose groups (p=0.01), intraprostatic DHT was comparable regardless of T dose (p=0.11) and 10-20-fold greater than intraprostatic T. Conclusions: In healthy, medically castrate men receiving exogenous T, the total intraprostatic androgen concentration (predominantly DHT) remained stable across serum T concentrations within the physiologic range. These findings further our knowledge of the relationship between serum and intraprostatic androgens and suggest physiologic serum T achieved by TRT is unlikely to alter the prostate hormonal milieu.
Article
Background Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. Methods We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials — the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. Results Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy–Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. Conclusions In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.)
Article
Purpose: To determine the effect of testosterone solution 2% on total testosterone level, and 2 symptoms of hypogonadism, sex drive and energy level. Materials and methods: This was a randomized, multi-center, double-blind, placebo-controlled, 16-week study to compare the effect of testosterone and placebo on the proportion of men having a testosterone level within the normal range (300-1050 ng/dL) upon treatment completion, and to assess the impact of testosterone on sex drive and energy level, measured using the Sexual Arousal, Interest, and Drive scale (SAID) and the Hypogonadism Energy Diary (HED), respectively. Males ≥18 years (N=715), with total testosterone <300 ng/dL and at least one symptom of testosterone deficiency (decreased energy, decreased sexual drive) were randomized to 60mg topical testosterone solution 2% or placebo once daily. Results: For study completers, 73% in the testosterone versus 15% in the placebo group had a testosterone level within the normal range at endpoint (p<0.001). Participants assigned testosterone showed greater baseline-to-endpoint improvement in SAID scores (low sex drive subset; p<0.001 versus placebo) and HED scores (low energy subset; p=0.02 versus placebo [not significant at pre-specified p<0.01]). No major adverse cardiovascular or venous thrombotic events were reported in the testosterone group; the incidence of increased hematocrit was higher with testosterone (p=0.04 versus placebo). Conclusions: Once-daily testosterone solution 2% for 12 weeks was efficacious in restoring normal testosterone levels and improving sexual drive in hypogonadal men. Improvement was also seen in energy levels on the HED though not at the pre-specified p<0.01. No new safety signals were identified.
Article
Sexual dysfunction and Opioid-Induced Sexual Hormone Deficiency (OPISHD) have been associated with patients on long-term opioid pain therapy. There have been few comprehensive reviews to establish a relation between hypogonadism with chronic opioid pain management. The OPISHD is often not treated and literature guiding this topic is scarce. To investigate hypogonadism associated with long-term opioid therapy based on qualitative data analysis of the available literature. Systematic review. The review included relevant literature identified through searches of PubMed, Cochrane, Clinical Trials, US National Guideline Clearinghouse, and EMBASE, for the years 1960 to September 2013. The quality assessment and clinical relevance criteria used were the Cochrane Musculoskeletal Review Group Criteria for randomized control trials and the Newcastle-Ottawa Scale Criteria for observational studies. The level of evidence was classified as good, fair, and poor, based on the quality of evidence. The primary outcome measures were clinical symptoms and laboratory markers of hypogonadism. Secondary outcome measure was management of OPISHD. Thirty-one studies were identified, of which 14 studies met inclusion criteria. There were no randomized control trials and eight of 14 studies were of moderate quality. The remaining studies were of poor quality. Four studies report most patients on long-term oral opioid therapy have associated hypogonadism and three studies of patients receiving intrathecal opioid therapy suggest that hypogonadism is common. There is lack of high-quality studies to associate chronic opioid pain management with hypogonadism. At present, there is fair evidence to associate hypogonadism with chronic opioid pain management, and only limited evidence for treatment of OPISHD.
Article
The fall in testosterone levels with age appears to be a real phenomenon. Declining testicular function and hypothalamic dysregulation appear to be the mechanisms explaining the fall in testosterone levels with age. The increased prevalence of obesity and chronic illness in ageing men both cause a large drop in testosterone levels independent of ageing. Age-related hypogonadism appears to be different to other 'classical' causes of hypogonadism. Testosterone levels are not unequivocally low and associated symptoms are non-specific. In frail older men with low testosterone levels, testosterone therapy appears to improve QOL and physical function. In less frail men, however, effects of testosterone therapy in the ageing male are small and/or inconsistent. There remains an urgent need for randomised clinical trials with sufficient size, duration and power to determine specific benefits and risks of testosterone therapy in older men. © The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Article
Symptomatic androgen deficiency is common in patients taking opioid analgesics, as these drugs potently suppress the hypothalamic-pituitary-gonadal axis. However, the efficacy of testosterone replacement in this setting remains unclear. The objective of this trial was to evaluate the efficacy of testosterone replacement on pain perception and other androgen-dependent outcomes in men with opioid-induced androgen deficiency. We conducted a randomized, double-blind, parallel placebo-controlled trial at an outpatient academic research center. Participants were men aged 18 to 64 years on opioid analgesics for chronic noncancer pain, and total testosterone levels were <350 ng/dL. Participants were randomly assigned to 14 weeks of daily transdermal gel that contained 5 g of testosterone or placebo. Primary outcomes were changes in self-reported clinical pain and objectively assessed pain sensitivity. Sexual function, quality of life, and body composition were also assessed. The mean age was 49 years. The median total and free testosterone levels at baseline were 243 ng/dL and 47 pg/mL and 251 ng/dL and 43 pg/mL in the testosterone and placebo arm, respectively. Of the 84 randomized participants, 65 had follow-up data on efficacy outcomes. Compared with men assigned to the placebo arm, those assigned to testosterone replacement experienced greater improvements in pressure and mechanical hyperalgesia, sexual desire, and role limitation due to emotional problems. Testosterone administration was also associated with an improvement in body composition. There were no between-group differences in changes in self-reported pain. In conclusion, in men with opioid-induced androgen deficiency, testosterone administration improved pain sensitivity, sexual desire, body composition, and aspects of quality of life.
Article
Introduction: This study investigated the effects of testosterone (T) treatment on cognition, mood, and quality of life in men with mild cognitive impairment (MCI) and low serum T levels. Methods: A total of 351 community-dwelling men were screened, and 37 men evidenced both MCI and low T of whom 27 agreed for further screening. Twenty-two met all the study inclusion/exclusion criteria and enrolled in a 6-month randomized, double-blind, placebo-controlled study. Results: Total T levels significantly increased in the T treatment group. No significant changes were observed in measures of cognition, mood, or quality of life other than improvement in 1 objective measure of verbal memory (P < .05) and decreased depression symptoms (P < .02) in the treatment group. Conclusions: Testosterone treatment may modestly improve verbal memory and depression symptoms in men with both MCI and low T.
Article
Purpose of review: To examine bone health in relation to testosterone and male hypogonadism. Recent findings: An emerging area of research pertains to the newly described bone-testis axis. In particular, the peptide hormone osteocalcin, which is made by bone and fat, appears to play a role in testosterone production. Inconsistent weak associations have been noted between vitamin D deficiency or insufficiency and lower testosterone levels. Although a high prevalence of hypogonadism is associated with opioid use, HIV and transfusion-dependent thalassemia, the risk of fracture in these populations is unclear. In fact, one study found that the modest increase in fractures among opioid users was attributed to central nervous system adverse effects of the medications as opposed to chronic hypogonadism. In terms of therapy, many small studies have found that testosterone replacement therapy increases bone mineral density in hypogonadal men, including men with hypopituitarism. Summary: Further research is needed on the cross-talk that occurs in the bone-testis axis. When it comes to managing men with hypogonadism, the benefit of testosterone replacement therapy on prevention of incident fractures is uncertain. Large, long-term randomized controlled trials are needed with fracture as the primary outcome.
Article
Introduction: The role of testosterone supplementation (TS) as a treatment for male sexual dysfunction remains questionable. Aim: The aim of this study was to attempt a meta-analysis on the effect of TS on male sexual function and its synergism with the use of phosphodiesterase type 5 inhibitor (PDE5i). Methods: An extensive Medline, Embase, and Cochrane search was performed. Main outcome measures: All randomized controlled trials (RCTs) comparing the effect of TS vs. placebo or the effect of TS as add on to PDE5is on sexual function were included. Data extraction was performed independently by two of the authors (A. M. Isidori and G. Corona), and conflicts resolved by the third investigator (M. Maggi). Results: Out of 1,702 retrieved articles, 41 were included in the study. In particular, 29 compared TS vs. placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5is. TS is able to significantly ameliorate erectile function and to improve other aspects of male sexual response in hypogonadal patients. However, the presence of possible publication bias was detected. After applying "trim and fill" method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completely supported by pharmaceutical companies (confidence interval [0.04-0.53] and [0.12; 0.52], respectively). In addition, we also report that TS could be associated with an improvement in PDE5i outcome. These results were not confirmed in placebo-controlled studies. The majority of studies, however, included mixed eugonadal/hypogonadal subjects, thus imparting uncertainty to the statistical analyses. Conclusions: TS plays positive effects on male sexual function in hypogonadal subjects. The role of TS is uncertain in men who are not clearly hypogonadal. The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias. New RCTs exploring the effect of TS in selected cases of PDE5i failure that persistently retain low testosterone levels are advisable.
Article
Objective To develop an understanding of hypogonadal men with a history of anabolic-androgenic steroid (AAS) use and to outline recommendations for management. Design Review of published literature and expert opinions. Intended as a meta-analysis, but no quality studies met the inclusion criteria. Setting Not applicable. Patient(s) Men seeking treatment for symptomatic hypogonadism who have used nonprescribed AAS. Intervention(s) History and physical examination followed by medical intervention if necessary. Main Outcome Measures(s) Serum testosterone and gonadotropin levels, symptoms, and fertility restoration. Result(s) Symptomatic hypogonadism is a potential consequence of AAS use and may depend on dose, duration, and type of AAS used. Complete endocrine and metabolic assessment should be conducted. Management strategies for anabolic steroid–associated hypogonadism (ASIH) include judicious use of testosterone replacement therapy, hCG, and selective estrogen receptor modulators. Conclusion(s) Although complications of AAS use are variable and patient specific, they can be successfully managed. Treatment of ASIH depends on the type and duration of AAS use. Specific details regarding a patient's AAS cycle are important in medical management.
Article
Introduction: Late-onset hypogonadism may impair quality of life and contribute to metabolic and cardiovascular comorbidity in aging men. Testosterone replacement therapy is effective in treating hypogonadism. However, for the millions of men with a history of prostate cancer, exogenous testosterone has long been considered contraindicated, even though little data in such men are available. Clarification of this safety issue could allow treatment to be considered for a sizeable segment of the aging male population. Aim: The aim of this study is to examine population-based utilization and impact of testosterone replacement therapy in men with prostate cancer. Methods: Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified 149,354 men diagnosed with prostate cancer from 1992 to 2007. Of those, 1181 (0.79%) men received exogenous testosterone following their cancer diagnosis. We used propensity scoring analysis to examine the effect of testosterone replacement on the use of salvage hormone therapy and overall and prostate cancer-specific mortality. Main outcome measures: We assessed overall mortality, cancer-specific mortality, and the use of salvage hormone therapy. Results: Following prostate cancer diagnosis, testosterone replacement was directly related to income and educational status and inversely related to age (all P < 0.001). Men undergoing radical prostatectomy and men with well-differentiated tumors were more likely to receive testosterone (all P < 0.001). On adjusted analysis, testosterone replacement therapy was not associated with overall or cancer-specific mortality or with the use of salvage hormone therapy. Conclusions: In this population-based observational study of testosterone replacement therapy in men with a history of prostate cancer, treatment was not associated with increased overall or cancer-specific mortality. These findings suggest testosterone replacement therapy may be considered in men with a history of prostate cancer, but confirmatory prospective studies are needed.
Article
To review the controversial issues of the Testosterone Deficiency Syndrome (TDS) with an emphasis on the concerns about the diagnosis. The relevant literature was reviewed with particular attention to matters related to the clinical manifestations of the syndrome, the need for biochemical assessment and questions of biological and analytical variation that have to be taken into account. Therapeutic options were also appraised. There are numerous difficulties with the clinical diagnosis of TDS due to the lack of specificity and subtlety of the manifestations when the degree of deficiency is not severe. Confirmation of the clinical impression requires laboratory evaluation but the choice of assays remains an unsettled issue although there is a general consensus that both free and bioavailable testosterone best reflect the degree of androgenicity. The laboratory diagnosis enjoys a great deal of credibility among clinicians but shortcomings in the interpretation of the assays need to be reiterated and the need for close collaboration between the clinician and the clinical biochemist is important for diagnostic accuracy. Even when the clinical picture is convincing, the laboratory may produce inconclusive results. The option of a therapeutic trial should be contemplated in this situation. Treatment options should be decided between the physician and the patient considering issues of availability, tolerance, efficacy and cost. TDS is a prevalent condition but a matter of persistent controversy due to the vagaries of the clinical and laboratory diagnosis. Symptomatic men with documented T deficiency deserve treatment to improve their quality of life.
Article
Sexual dysfunction, particularly erectile dysfunction (ED), is common in men with type 2 diabetes, occurring in up to 75% of cases. The prevalence of hypogonadism is also high in men with diabetes and low testosterone is associated with both sexual dysfunction and a reduced response to oral therapy for ED. This study aimed to determine the effect of testosterone replacement with long-acting Testosterone Undecanoate (TU) on sexual function, mood and quality of life vs. placebo over a treatment period of 30 weeks followed by 52 weeks of open-label medication. The study was conducted in a primary care population of men with type 2 diabetes attending their primary care physician for routine visits. The male diabetic populations of seven general practices were screened at routine diabetes visits to detect symptomatic men with total testosterone levels of 12 nmol/L or less or with free testosterones of 250 pmol/L or less. Two hundred eleven men were screened. A double-blind placebo-controlled study was conducted in 199 men with type 2 diabetes and hypogonadism treated for 30 weeks with either 1,000 mg of TU or matching placebo followed by 52-week open-label follow on. The primary outcome measure, International Index of Erectile Function (IIEF), was used to evaluate sexual dysfunction, and the Ageing Male Symptom (AMS), Hospital Anxiety and Depression Scale, and Global Efficacy Question were used as secondary outcome measures to assess mood and self-reported quality of life. Testosterone replacement therapy with long-acting TU improved all domains of sexual function at 30 weeks (erectile function [EF], P = 0.005; intercourse satisfaction, P = 0.015; sexual desire, P = 0.001; overall satisfaction, P = 0.05; and orgasm, P = 0.04), with benefit as early as 6 weeks. Improvements in AMS score were significant in men without depression (P = 0.02) and the presence of depression at baseline was associated with marked reduction in response to both sexual function and psychological scores. All responses in sexual function continued to improve significantly up to 18 months with an improvement in EF score of 4.31 from baseline. In a small cohort of 35 men taking phosphodiesterase type 5 inhibitors, there was no change during the double-blind phase but a nine-point improvement in EF domain during 52-week open-label treatment. After 30 weeks, 46% vs. 17% of patients on active therapy vs. placebo felt that the treatment had improved their health, reaching 70% after open-label therapy. Less obese and older patients responded better to testosterone therapy. There were no significant adverse events. TU significantly improved all domains of the IIEF and patient reported quality of life at 30 weeks and more significantly after 52-week open-label extension. Improvement was most marked in less obese patient and those without coexisting depression. In men with type 2 diabetes, trials of therapy may need to be given for much longer than 3–6 months suggested in current guidelines.
Article
Objective: This study analyzed the effects of normalization of serum testosterone (T) levels on anthropometric parameters in hypogonadal men. Design and methods: Open-label, single-center, cumulative, prospective registry study of 255 men (aged 33-69 years, mean 58.02 ± 6.30 years), with T levels below 12.13 nmol/L (mean: 9.93±1.38). 215 men for at least 2 years, 182 for 3 years, 148 for 4, and 116 for at least 5 years were studied. They received parenteral T undecanoate 1,000 mg/12 weeks after an initial interval of 6 weeks. Results: Body weight (BW) decreased from 106.22 ± 16.93 kg to 90.07 ± 9.51 kg. Waist circumference (WC) reduced from 107.24 ± 9.14 cm to 98.46 ± 7.39 cm. BMI (m/kg(2) ) declined from 33.9 ± 5.51 m/kg(2) to 29.13 ± 3.09 m/kg(2) . All parameters examined were statistically significant with P < 0.0001 versus baseline and versus the previous year over 5 years indicating a continuous weight loss over the full observation period. The mean per cent weight loss after 1 year was 4.16 ± 0.31%, after 2 years 7.54 ± 0.32%, after 3 years 9.23 ± 0.33%, after 4 years 11.42 ± 0.35% and after 5 years 13.57 ± 0.37%. Conclusions: In an uncontrolled, observational cohort, normalizing serum T to normal physiological levels produced consistent loss of BW, WC, and BMI. These improvements were progressive over the full 5 years of the study.
Article
Introduction. Morbidity/mortality is higher in men with below-normal serum testosterone. Restoring testosterone to normal is beneficial. Aim. Assessment of safety and effectiveness of injectable long-acting testosterone undecanoate (TU) in hypogonadal men in daily clinical practice. Methods. An international, multicenter, one-arm, prospective observational study in 23 countries. Main Outcome Measures. Parameters of erectile function, libido, vigor/vitality, mood, and ability to concentrate assessed by physician interview using items and five-point Likert scales. Physical and circulatory parameters as well as hematocrit, prostate-specific antigen (PSA) levels, glucose control, and lipid profiles. IPASS. An International, multicenter, Post-Authorisation (after authorized use in respective country) Surveillance Study on long-acting-intramuscular TU conducted at 155 centers in 23 countries in Europe, Asia, Latin America, and Australia. Patients received up to five TU injections during 9–12 months. Results. Of the 1,493 hypogonadal men enrolled, 1,438 (aged 49.2 ± 13.9 years) having received 6,333 injections were analyzed. Scores of mental and psychosexual functions (libido, vigor, overall mood, and ability to concentrate) improved markedly, while mean waist circumference decreased from 100 to 96 cm. Blood pressure and lipid parameters were altered in a favorable and significant manner. After four TU injection intervals, the percentage of patients with “low” or “very low” levels of sexual desire/libido decreased from 64% at baseline to 10%; moderate, severe, or extremely severe erectile dysfunction decreased from 67% to 19%. At the last observation, 89% of patients were “satisfied” or “very satisfied” with TU therapy. Adverse events and adverse drug reactions (ADRs) occurred in 12% and 6% of patients, respectively, mostly mild to moderate. The most common ADRs were increase in hematocrit, increase in PSA, and injection site pain (all <1%). No case of prostate cancer was observed. Conclusion. In this largest worldwide sample of hypogonadal men, injectable long-acting TU was effective and well tolerated. Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, and Maggi M. IPASS: A study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. J Sex Med **;**:**–**.
Article
Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Prostate growth is ruled by testosterone. Nevertheless, the paradigm that high testosterone levels induce prostate cancer development or lead to a poor prognosis in prostate cancer is not supported by evidence. A growing number of studies suggest that, on the contrary, low testosterone levels are related to poor prognosis features in prostate cancer such as higher prostate-specific antigen or higher Gleason score. Our experience shows that testosterone levels are related to risk of progression of prostate cancer – those men with lower testosterone levels are at higher risk of progression of their prostate cancer after treatment delivery.
Article
To verify whether hypogonadism represents a risk factor for cardiovascular (CV) morbidity and mortality and to verify whether testosterone replacement therapy (TRT) improves CV parameters in subjects with known CV diseases (CVDs). Meta-analysis. An extensive Medline search was performed using the following words 'testosterone, CVD, and males'. The search was restricted to data from January 1, 1969, up to January 1, 2011. Of the 1178 retrieved articles, 70 were included in the study. Among cross-sectional studies, patients with CVD have significantly lower testosterone and higher 17-β estradiol (E(2)) levels. Conversely, no difference was observed for DHEAS. The association between low testosterone and high E(2) levels with CVD was confirmed in a logistic regression model, after adjusting for age and body mass index (hazard ratio (HR)=0.763 (0.744-0.783) and HR=1.015 (1.014-1.017), respectively, for each increment of total testosterone and E(2) levels; both P<0.0001). Longitudinal studies showed that baseline testosterone level was significantly lower among patients with incident overall- and CV-related mortality, in comparison with controls. Conversely, we did not observe any difference in the baseline testosterone and E(2) levels between case and controls for incident CVD. Finally, TRT was positively associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression. Lower testosterone and higher E(2) levels correlate with increased risk of CVD and CV mortality. TRT in hypogonadism moderates metabolic components associated with CV risk. Whether low testosterone is just an association with CV risk, or an actual cause-effect relationship, awaits further studies.
Article
Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men. TT was measured using liquid chromatography tandem mass spectrometry in nonobese healthy men, 19-40 yr old, in the Framingham Heart Study Generation 3; FT was calculated. Values below the 2.5th percentile of reference sample were deemed low. We determined the association of low TT and FT with physical dysfunction, sexual symptoms [European Male Aging Study (EMAS) only], and diabetes mellitus in three cohorts: Framingham Heart Study generations 2 and 3, EMAS, and the Osteoporotic Fractures in Men Study. In a reference sample of 456 men, mean (sd), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes. Reference ranges generated in a community-based sample of men provide a rational basis for categorizing testosterone levels as low or normal. Men with low TT or FT by these criteria had higher prevalence of physical dysfunction, sexual dysfunction, and diabetes. These reference limits should be validated prospectively in relation to incident outcomes and in randomized trials.
Article
Late-onset hypogonadism describes the co-occurrence of a range of physical, psychological and sexual symptoms in aging men, with the implication that these symptoms are caused by androgen deficiency. Previous investigations examined mostly population samples and did not take into account the testosterone modulating effects of the genetically determined CAG repeat polymorphism (CAGn) of the androgen receptor (AR) gene. This is the first study which investigates aging male symptoms (AMS) in relation to the genetically determined androgen receptor CAG polymorphism, estradiol and testosterone levels in men > or =50 years of age in a healthy population sample (n=100), outpatients of an andrological department (n=76) who presented with sexual and "aging male" symptoms and a psychosomatic/psychiatric sample (n=120) who presented with various psychological and medically unexplained somatic complaints. Although the population sample was significantly older than the two patient groups, they reported significantly fewer AMS and had higher testosterone levels and shorter CAG repeats of the AR. Regression analysis revealed influences of CAGn on the AMS global score and the psychological and somatic subscale only in the two patient samples, while testosterone had some impact on the sexual subscale. Our results suggest that the so-called aging male symptoms show a certain association to androgenicity, but that they are rather unspecific and of multifactorial origin. Other factors contributing to AMS need further clarification.
Article
Though mass spectrometry (MS) assays are increasingly used for routine clinical measurements of serum total testosterone (TT), information about the variability of results is limited. This study assessed the variability of TT measurement results from routine MS assays. Twenty serum samples (12 females, 8 males) were analyzed on 2 days by seven high performance liquid chromatography (HPLC), and one gas chromatography (GC)-tandem mass spectrometry (HPLC-MS/MS, GC-MS/MS) assays. Two samples (male and female) were provided in five replicates to assess the within-run variability. Results were compared against those obtained at National Institute of Standards and Technology (NIST). The within- and between-laboratory variability was assessed for each sample. Comparisons to the NIST results were performed using bias plot and Deming regression analysis. The overall coefficient of variation of the results obtained with MS assays was <15%CV at >1.53 nmol/L and <34%CV at 0.3 nmol/L. The between-assay variability was the major contributor to the overall variability. The assay precision was the highest (<3%CV) with assays using liquid-liquid extraction for sample preparation or GC-MS/MS. The mean percent difference to the reference assay was 11%. The slopes of Deming regression analysis of the MS assays were between 0.903 and 1.138 (correlation coefficient: >0.996). TT concentrations for one assay were above the measurement range. The variability of TT measurement results among MS assays is substantially smaller than that reported for immunoassays. The type of sample preparation may affect assay precision. Standardizing assays can further reduce the variability of measurement results.
Article
To examine the effect of graded doses of testosterone on physical function and muscle performance in healthy, older men. Randomized, double-blind, placebo-controlled clinical trial. General clinical research center. Community-dwelling healthy men aged 60 to 75 (N=44). Monthly treatment with a gonadotropin-releasing hormone agonist plus 25, 50, 125, or 300 mg/wk of intramuscular injections of testosterone enanthate for 20 weeks. Skeletal muscle mass (SMM) was estimated using dual-energy X-ray absorptiometry. Leg press strength was measured by one repetition maximum, leg power by Nottingham Leg Rig, and muscle fatigability by repetitions to failure in the leg press exercise. Stair climbing, 6-meter and 400-meter walking speed, and a timed-up-and-go (TUG) test were used to assess physical function. Significant testosterone dose- and concentration-dependent increases were observed in SMM (P<.001) and maximal strength (P=.001) but not muscle fatigability. Leg power also increased dose-dependently (P=.048). In contrast, changes in self-selected normal and fast walking speed over 6 or 400 meters, stair climbing power, and time for the TUG were not significantly related to testosterone dose, testosterone concentrations, or changes in muscle strength or power, or SMM. Testosterone administration was associated with dose-dependent increases in SMM, leg strength, and power but did not improve muscle fatigability or physical function. The observation that physical function scores did not improve linearly with strength suggests that these high-functioning older men were already in the asymptotic region of the curve describing the relationship between physical function and strength.
Article
We reviewed the results of serum testosterone and prolactin determination in 1,022 patients referred because of erectile dysfunction and compared the data with history, results of physical examination, other etiological investigations and effects of endocrine therapy to refine the rules of cost-effective endocrine screening and to pinpoint actual responsibility for hormonal abnormalities. Testosterone and prolactin were determined by radioimmunoassay. Every patient was screened for testosterone and 451 were screened for prolactin on the basis of low sexual desire, gynecomastia or testosterone less than 4 ng./ml. Determination was repeated in case of abnormal first results. Prolactin results were compared with those of a previous personal cohort of 1,340 patients with erectile dysfunction and systematic prolactin determination. Main clinical criteria tested regarding efficiency in hormone determination were low sexual desire, small testes and gynecomastia. Endocrine therapy consisted of testosterone heptylate or human chorionic gonadotropin for hypogonadism and bromocriptine for hyperprolactinemia. Testosterone was less than 3 ng./ml. in 107 patients but normal in 40% at repeat determination. The prevalence of repeatedly low testosterone increased with age (4% before age 50 years and 9% 50 years or older). Two pituitary tumors were discovered after testosterone determination. Most of the other low testosterone levels seemed to result from nonorganic hypothalamic dysfunction because of normal serum luteinizing hormone and prolactin and to have only a small role in erectile dysfunction (definite improvement in only 16 of 44 [36%] after androgen therapy, normal morning or nocturnal erections in 30% and definite vasculogenic contributions in 42%). Determining testosterone only in cases of low sexual desire or abnormal physical examination would have missed 40% of the cases with low testosterone, including 37% of those subsequently improved by androgen therapy. Prolactin exceeded 20 ng./ml. in 5 men and was normal in 2 at repeat determination. Only 1 prolactinoma was discovered. These data are lower than those we found during the last 2 decades (overall prolactin greater than 20 ng./ml. in 1.86% of 1,821 patients, prolactinomas in 7, 0.38%). Bromocriptine was definitely effective in cases with prolactin greater than 35 ng./ml. (8 of 12 compared to only 9 of 22 cases with prolactin between 20 and 35 ng./ml.). Testosterone was low in less than 50% of cases with prolactin greater than 35 ng./ml. Low prevalences and effects of low testosterone and high prolactin in erectile dysfunction cannot justify their routine determination. However, cost-effective screening strategies recommended so far missed 40 to 50% of cases improved with endocrine therapy and the pituitary tumors. We now advocate that before age 50 years testosterone be determined only in cases of low sexual desire and abnormal physical examination but that it be measured in all men older than 50 years. Prolactin should be determined only in cases of low sexual desire, gynecomastia and/or testosterone less than 4 ng./ml.
Article
It is now well established that testosterone levels decline with age. What has not been established is whether the decline in testosterone is associated with a symptom complex. This study examined whether certain symptoms are more commonly present in males with low bioavailable testosterone (BT) levels. These were used to evaluate a questionnaire for androgen deficiency in aging males (ADAM). The validity of the ADAM questionnaire to screen for low BT was tested in 316 Canadian physicians aged 40 to 62 years. Low BT levels were present in 25% of this population. None had elevated luteinizing hormone (LH) levels. The ADAM questionnaire had 88% sensitivity and 60% specificity. When the questionnaire was administered twice 2 to 4 weeks apart to 10 men, it was determined that the coefficient of variation was 11.5%. In a second study of 34 ADAM-positive patients, 37% of those with clearly normal BT levels demonstrated some evidence of dysphoria. Finally, in 21 patients who were treated with testosterone, improvement on the ADAM questionnaire was demonstrated in 18 (P = .002). These data support the concept of a symptom complex associated with low BT levels in aging males. In addition, the ADAM questionnaire appears to be a reasonable screening questionnaire to detect androgen deficiency in males over 40 years of age.
Article
To design a self-administered screening questionnaire to inform men about their risk for testosterone deficiency. The screener was developed in two phases. First was a construction phase in which relevant risk factors and a scoring algorithm were defined from multiple logistic regression analyses of survey data. In the second phase, the screener's accuracy (based on sensitivity, specificity, and Receiver Operating Characteristic (ROC) curves) was tested using patients from a primary care clinic. All subjects provided blood samples for endocrine testing. Survey data from 1660 men aged 40–79 years participating in the Massachusetts Male Ageing Study (MMAS) were analysed in the first phase. The clinic sample consisted of 304 men aged 40–79 years presenting at a large Massachusetts primary health care clinic for routine check-ups or minor medical problems. The primary outcome was testosterone deficiency, defined as serum total testosterone below 12·1 nmol/l. Self-reported variables considered as potential risk factors included age, obesity, chronic diseases, health behaviour, the Jackson dominance scale, and symptoms of stress. The prevalence of testosterone deficiency was 20·4% in the MMAS and 42·1% in the clinic sample. An eight-item screener was developed based on age, body mass index, diabetes, asthma, headaches, sleep patterns, dominance preferences, and smoking status. The screener performed significantly better than chance in identifying men with low testosterone levels; the area under the ROC curve was 0·66 in the MMAS sample and 0·67 in the clinic sample. The self-scored screener developed in this study reliably detects men at risk of hypogonadism. The screener encourages at risk men to seek professional evaluation of their testosterone levels.
Article
The androgen testosterone and its metabolite dihydrotestosterone exert their effects on gene expression and thus effect maleness via the androgen receptor (AR). A diverse range of clinical conditions starting with complete androgen insensitivity has been correlated with mutations in the AR. Subtle modulations of the transcriptional activity induced by the AR have also been observed and frequently assigned to a polyglutamine stretch of variable length within the N-terminal domain of the receptor. This stretch is encoded by a variable number of CAG triplets in exon 1 of the AR gene located on the X chromosome. First observations of pathologically elongated AR CAG repeats in patients with X-linked spino-bulbar muscular atrophy showing marked hypoandrogenic traits were supplemented by partially conflicting findings of statistical significance also within the normal range of CAG repeat length: an involvement of prostate tissue, spermatogenesis, bone density, hair growth, cardiovascular risk factors and psychological factors has been demonstrated. The highly polymorphic nature of glutamine residues within the AR protein implies a subtle gradation of androgenicity among individuals within an environment of normal testosterone levels providing relevant ligand binding to ARs. This modulation of androgen effects may be small but continuously present during a man's lifetime and, hence, exerts effects that are measurable in many tissues as various degrees of androgenicity and represents a relevant effector of maleness. It remains to be elucidated whether these insights are important enough to become part of individually useful laboratory assessments.
Article
No clinical study data in which the AMS scale was applied as outcome measure has been reported until today. An open post-marketing study was performed by office-based urologists in Germany in 2000/01. We analysed data of 1174 androgen-deficient males who were treated with testosterone enanthate. The AMS scale was applied prior to and after 12 weeks treatment. The improvement of complaints during treatment relative to the baseline score was 32% on average. Patients with little or no symptoms before therapy improved by 11%, those with mild complaints at entry by 24%, with moderate by 31%, and with severe symptoms by 39% compared with the baseline score. We showed that the distribution of complaints of testosterone-deficient men before therapy almost returned to norm values after 12 weeks of testosterone treatment. We also demonstrated that the AMS results can predict the independent (physician's) opinion about the individual treatment effect. The positive predictive value was 89%, the negative predictive value 59%, sensitivity (correct prediction of a positive assessment by the urologist) 96%, however, the specificity (correct prediction of a negative assessment by the physician) was only 30%. The AMS scale showed a convincing ability to measure treatment effects on quality of life across the full range of severity of complaints. In addition, results of the scale can predict the subjective clinical expert opinion on the treatment efficiency.
Article
We documented the experience of 2 urology practices with the use of testosterone supplementation to treat hypogonadal men who had undergone curative radical prostatectomy for localized prostate cancer. We also reviewed the literature for reports of the use of testosterone in men surgically cured of prostate cancer. A retrospective review of clinical records of 2 busy private urology practices was used to compile brief case histories of hypogonadal men treated with testosterone who had undergone curative radical prostatectomy for localized prostate cancer. Using MEDLINE and BIOSIS Previews (Biological Abstracts, Inc., Philadelphia, Pennsylvania), the literature was searched for articles describing the use of testosterone in men surgically cured of organ confined prostate cancer. The case records of 7 hypogonadal men who had undergone curative radical prostatectomy were identified. All men had clinical symptoms of hypogonadism and low serum testosterone levels. Each man was treated with an androgen preparation. After variable followup periods no biochemical or clinical evidence of cancer recurrence was found in any of the group. No reports in the literature were found of a similar therapeutic approach for such patients. Based on the clinical experience with this small group of men, and indirect evidence of the safety of this approach from epidemiological and clinical data, further cautious use of testosterone in a carefully selected population seems warranted.
Article
Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between "substitutive" and "pharmacological" androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of these men were not androgen deficient. Most consistent effects of treatment have been on body composition, but to date there is no evidence-based documentation of clinical benefits of androgen administration to elderly men with normal or moderately low serum testosterone in terms of diminished morbidity or of improved survival or quality of life. Until the long-term risk-benefit ratio for androgen administration to elderly is established in adequately powered trials of longer duration, androgen administration to elderly men should be reserved for the minority of elderly men who have both clear clinical symptoms of hypogonadism and frankly low serum testosterone levels.
Article
Objectives: Ageing in men is associated with a gradual decline in serum testosterone levels and a concomitant loss of muscle mass, accumulation of central adiposity, impaired mobility and increased risk of bone fractures. Whether androgen treatment might be beneficial in these subjects is still under debate. We have carried out a systematic review of randomized controlled trials (RCTs) evaluating the effects of testosterone (T) administration to middle-aged and ageing men on body composition, muscle strength, bone density, markers of bone metabolism and serum lipid profile. Data source: A comprehensive search of all published randomized clinical trials was performed using the MEDLINE, Cochrane Library, EMBASE and Current Contents databases. Review methods: Guided by prespecified criteria, software-assisted data abstraction and quality assessed by two independent reviewers, 29 RCTs were found to be eligible. For each investigated variable, we reported the results of pooled estimates of testosterone treatment using the random effect model of meta-analysis. Heterogeneity, reproducibility and consistency of the findings across studies were explored using sensitivity and meta-regression analysis. Results: Overall, 1,083 subjects were evaluated, 625 randomized to T, 427 to placebo and 31 to observation (control group). Weighted mean age was 64.5 years (range 49.9--77.6) and mean serum testosterone was 10.9 nmol/l (range 7.8--19). Testosterone treatment produced: (i) a reduction of 1.6 kg (CI: 2.5--0.6) of total body fat, corresponding to -6.2% (CI: 9.2--3.3) variation of initial body fat, (ii) an increase in fat free mass of 1.6 kg (CI: 0.6--2.6), corresponding to +2.7% (CI: 1.1--4.4) increase over baseline and (iii) no change in body weight. The effects of T on muscle strength were heterogeneous, showing a tendency towards improvement only at the leg/knee extension and handgrip of the dominant arm (pooled effect size=0.3 standard mean difference (SMD), CI: -0.0 to 0.6). Testosterone improved bone mineral density (BMD) at the lumbar spine by +3.7% (CI: 1.0--6.4%) compared to placebo, but not at the femoral neck, and produced a consistent reduction in bone resorption markers (pooled effect size = -0.6 SMD, CI: -1.0 to -0.2). Testosterone also reduced total cholesterol by 0.23 mmol/l (CI: -0.37 to -0.10), especially in men with lower baseline T concentrations, with no change in low density lipoprotein (LDL)-cholesterol. A significant reduction of high density lipoprotein (HDL)-cholesterol was found only in studies with higher mean T-values at baseline (-0.085 mmol/l, CI: -0.017 to -0.003). Sensitivity and meta-regression analysis revealed that the dose/type of T used, in particular the possibility of aromatization, explained the heterogeneity in findings observed on bone density and HDL-cholesterol among studies. Conclusion: The present analysis provides an estimate of the average treatment effects of testosterone therapy in middle-aged men. Our findings are sufficiently strong to justify further interventional studies focused on alternative targets of androgenic treatment carrying more stringent clinical implications, in particular the cardiovascular, metabolic and neurological systems.
Article
Although attention and concern about health disorders in aging men have been growing, the structure of psychological and somatic complaints of actual patients, not population-based cohorts, has not been elucidated in relation to sex hormone patterns and metabolism. The objective of the study was investigation of factors influencing complaint structures in aging male patients. This was a cross-sectional cohort study. The study was conducted in an andrological outpatient department. Subjects included 434 consecutive male patients aged 50-86 yr. The following hypotheses were measured: 1) psychosomatic complaints and metabolic factors in aging male patients are related to sex hormone levels in a symptom-specific manner, and 2) patients form subcohorts. A clear-cut threshold for late-onset hypogonadism was not found; rather, prevalence of psychosomatic symptoms and metabolic risk factors accumulated with decreasing androgen levels. For example, androgen-induced prevalence of loss of libido or vigor increased below testosterone concentrations of 15 nmol/liter (P < 0.001), whereas depression and diabetes mellitus type 2 (also in nonobese men) were significantly more present in men with testosterone concentrations below 10 nmol/liter (P < 0.001). Erectile dysfunction was identified as a composite pathology of metabolic risk factors, smoking, and depressivity, whereas only testosterone concentrations below 8 nmol/liter contributed to that symptom (P = 0.003). Cluster analysis revealed aging men to present within three independent groups characterized by psychosomatic complaints, metabolic disorders, and sexual health problems. These subgroups of patients exhibit distinct features in terms of androgen levels, age, and body mass index. There is no evidence that a uniform structure of testosterone concentrations and complaints exists within the cohort of elderly male patients. Rather, in aging male patients, psychosomatic complaints and metabolic risk relate to testosterone in a symptom-specific manner.