Classical Hypogonadism Research Articles

TRACK_9: Testosterone replacement assessment: Classical vs. functional hypogonadism-knowledge from a 9-year study.

The longitudinal efficacy and clinical utility of Testosterone Therapy (TTh) in ameliorating functional hypogonadism (FH) remain contentious, with long-term data being scarce. To address this lacuna, a comprehensive long-term registry study, stratifying patients across a spectrum of hypogonadal etiologies, offers a robust investigative paradigm. This 9-year registry, encompassing 650 patients (equivalent to 4,362 cumulative years of treatment), included 188 patients diagnosed with FH (mean age 42.3±11.3 years) and 462 individuals with classical hypogonadism (CH). The cohort segregated into 266 men with primary hypogonadism (PH, mean age 34.0±11.7 years) and 196 with secondary hypogonadism (SH, mean age 31.9±12.0 years). Uniform treatment across the cohort involved intramuscular administration of testosterone undecanoate (1,000mg). A comparative analysis was conducted focusing on anthropometric, metabolic, and safety parameters. Serum testosterone levels increased from 6.6±2.4 to 19.3±2.9nmol/L (p<0.001). TTh was linked with weight reduction and decreased waist circumference (WC) in both CH and FH cohorts (both p<0.001). Cox regression and Kaplan-Meier analyses delineated disparities: men with FH demonstrated a higher propensity for losing>10% body weight and>5% WC compared to CH (hazard ratio [HR] 1.3 [1.1-1.4], p=0.008 and HR 1.4 [1.3-1.5], p=0.001). Increases in hematocrit>50% were uniform across groups, albeit amelioration of anemia was more pronounced in FH versus CH (p=0.002). Increments of prostate-specific antigen (PSA) levels were more likely to occur in FH (HR 1.3 [1.1-1.6], p=0.003). FH patients exhibited pronounced improvements in metabolic parameters and in aging male symptom score (AMS) and IIEF-EF questionnaire scores. These effects were markedly modulated by age and initial weight. Subgroup analysis of age-matched obese patients revealed an accentuated impact of TTh in CH compared to FH. The therapeutic outcomes of TTh across distinct hypogonadal populations demonstrate heterogeneous responses, significantly influenced by diagnostic categorization, age, and baseline risk factor profiles.

FRI444 Testosterone Therapy in Men with Classical vs Functional Hypogonadism: Results from a Controlled 9-year, Real-world Registry Study

Abstract Disclosure: M. Zitzmann: None. Background and Significance: Long-term data on Testosterone therapy (TTh) in hypogonadal men are limited and the clinical value, especially in men with functional hypogonadism (FH) is debated. A long-term, real-world registry study comprising groups of patients with hypogonadism of various etiologies provides a suitable and novel approach to this clinical issue. Methods: A registry spanning 9 years comprising 650 patients with hypogonadism included 188 patients with FH (mean age 42.3±11.3 years) and 462 men with classical hypogonadism (CH). Of these, 266 men had primary hypogonadism (PH, mean age 34.0±11.7 years) and 196 secondary hypogonadism (SH, mean age 31.9±12.0 years). All men uniformly received intramuscular T undecanoate (1000 mg). Effects of TTh on anthropometric parameters, as well as metabolic and safety parameters were compared. Results: The registry contained metabolic and safety parameters in individual duration of TTh spanning 1 to 9 years. Serum T concentrations increased from 6.6±2.4 nmol/L to 19.3±2.9 nmol/L in all patients (duration-of-treatment-dependent averages, mixed linear model for repeated measurements with the fixed variable “time x visit interaction”: p&amp;lt;0.001). In both categories of hypogonadism, TTh was associated with significant weight loss and decrease in waist circumference (WC, both p&amp;lt;0.001). Cox regression and Kaplan-Meier models revealed differences of inter-individual check-points: men with FH were more likely to lose &amp;gt;10% weight and &amp;gt;5% of WC than men with CH (hazard ratio 1.3 [1.1-1.4], p=0.008 and hazard ratio 1.4 [1.3-1.5], p=0.001). There was no difference between groups for the overall marked increase in hematocrit. Changes in PSA levels were more likely to occur in FH (hazard ratio 1.3 [1.1-1.6], p=0.003). During TTh, patients with FH exhibited significantly more pronounced changes of favourable nature in metabolic parameters than patients with CH (total cholesterol, triglycerides, LDL- and HDL-cholesterol and fasting glucose). The same applied to scores of AMS and IIEF-EF questionnaires. Effects on most parameters, especially hematocrit, were significantly modulated by age and baseline values for weight, WC und T. Conclusions: Findings regarding effects and safety of TTh in different groups of hypogonadal men are provided. Effects on factors associated with cardiovascular health are modulated by diagnosis and age. Patients with FH seem to benefit to a larger extent from TTh, most likely attributable to their more pronounced risk factor profile at baseline. Presentation Date: Friday, June 16, 2023

Approach to the Patient: The Evaluation and Management of Men ≥50 Years With Low Serum Testosterone Concentration.

Although testosterone replacement in men with classic hypogonadism due to an identified pathology of the hypothalamic-pituitary-testicular axis is uncontroversial, the role of testosterone treatment for men with age-related declines in circulating testosterone is unclear. This is due to the lack of large, long-term testosterone therapy trials assessing definitive clinical endpoints. However, men ≥50 years of age, particularly those who have a body mass index >25 kg/m2 and multiple comorbidities, commonly present with clinical features of androgen deficiency and low serum testosterone concentrations. Clinicians are faced with the question whether to initiate testosterone therapy, a difficult dilemma that entails a benefit-risk analysis with limited evidence from clinical trials. Using a case scenario, we present a practical approach to the clinical assessment and management of such men.

The HEAT-Registry (HEmatopoietic Affection by Testosterone): comparison of a transdermal gel vs long-acting intramuscular testosterone undecanoate in hypogonadal men

Context Testosterone (T) therapy of hypogonadal men requires stable kinetics, tolerance and attenuation of symptoms. Both intramuscular injections of the long-acting ester T undecanoate (TU) and transdermal application of T gel offer a proven efficacy. As T has marked effects on hematopoiesis, an elevation of hematocrit has to be considered during T therapy. Objective To compare the effects of a transdermal T gel with long-acting intramuscular TU on hematopoiesis, controlling for age, diagnosis, androgen receptor susceptibility and obesity. Design Prospective two-arm open registry, minimum duration of 26 weeks per patient. Putative modulators of erythropoiesis entering regression models were type of medication, type of hypogonadism, delta of total testosterone concentrations, waist circumference, age as well as (in a sub-group) androgen receptor gene CAG repeat length. Setting Tertiary university based andrological outpatient department. Patients 802 hypogonadal men, 498 receiving T gel and 304 receiving intramuscular TU, median age 40 years (interquartile range = 25). Results Follow-up visits after initiation of treatment occurred between treatment weeks 26-30. Serum T concentrations increased markedly in both patient groups. Men receiving intramuscular TU exhibited an increased hematocrit (>50%) to a significantly higher amount than men receiving T gel (69/304 vs. 25/498, p < 0.001). Corresponding results were seen for higher values of hematocrit (>52% and >54%). Advanced age (p = 0.009), higher waist circumference (p = 0.01), higher delta testosterone (p = 0.007) and functional vs classical hypogonadism (p = 0.04) contributed to the effect in stepwise multiple regression models. Attenuated androgen action (longer androgen receptor CAG repeats) mitigated the effect (p = 0.01) in a subgroup of 574 patients. Men with anemia (hemoglobin ≤12.7 g/dl) were more likely to move out of the pathological range when receiving TU vs T gel (41/53 vs. 49/89 p = 0.01). Conclusions T substitution with intramuscular TU or T gel increase T concentrations effectively. Long-acting TU leads to a higher rate of hematocrit levels >50%, whilst at the same time it seems to be more efficient to ameliorate anemia in the subgroup of respectively affected hypogonadal patients . This applies especially to obese older men with functional hypogonadism.

Age-Related Testosterone Deficiency Merits Treatment

The negative effects of testosterone deficiency (TD) on human health and quality of life are well demonstrated, including signs, symptoms, metabolic syndrome, obesity, and increased mortality. Recently, substantial evidence emerged, demonstrating the benefits of testosterone therapy in men with classical and “age-related” hypogonadism. The US Food and Drug Administration (FDA) opposes testosterone therapy in men with age-related hypogonadism but not in men with classical hypogonadism. The FDA acknowledges that TD merits treatment, but the FDA made an artificial distinction between diagnoses where T treatment is warranted and others where the underlying diagnosis is unknown, and treatment is unwarranted. The FDA labeled the unknown category as “age-related.” Since the FDA is unable to demonstrate that one group differs in benefits or risks from the other, there are no bases for this distinction. This action by the FDA is not based on scientific or clinical evidence. There is no evidence that the response to testosterone therapy of “age-related” hypogonadism occurs via different physiological or biochemical mechanisms than those historically recognized conditions. Also, there is no evidence that “age-related” hypogonadism responds less well to testosterone therapy than “classical” hypogonadism. More importantly, there is no scientific or clinical evidence to suggest that the risks of testosterone therapy in men with “age-related” hypogonadism are worse or different for men with “classical” hypogonadism. For these reasons, we disagree with the FDA position on testosterone therapy in age-related hypogonadism.

SAT-LB5 Prevalence of Hypogonadism in Young Obese Males

Ageing, obesity, and chronic illness are major factors affecting serum testosterone (T) levels in men.The magnitude of the impact of ageing on serum T levels is well established, for obesity this is less clear. Severe obesity may lead to isolated hypogonadotropic hypogonadism (IHH). Several explanations have been offered to clarify the presence of reduced T levels in obese men. One relates to the technique that is generally employed to measure serum androgen levels, i.e. measurement of total testosterone (TT) instead of free testosterone (FT). TT represents the sum of FT and T bound to albumin and sex hormone binding globulin (SHBG). A profound reduction in SHBG level is commonly found in obese men, and this is a major factor causing a decrease in TT.Measurement of free testosterone levels may provide a more accurate assessment of androgen status than the (usually preferred) measurement of total testosterone in situations where SHBG levels are outside the reference range. However, reference ranges for free testosterone levels are not well established, especially in older men, and some have argued that the measurement of free testosterone levels merely reintroduces age in a covert form. This is a cross sectional study to estimate prevalence of hypogonadism in young obese males. In this study 147 young obese men participated, of which we confirmed low total testosterone (TT) levels in 35.37% of subjects with a p value of 0.06. Since only Total Testosterone was measured for categorizing subjects with or without hypogonadism, Free Testosterone measurement would be a better indicator for the diagnosis of hypogonadism as in cases where the total testosterone is borderline-low or when SHBG concentrations are abnormal. As such, the study is valuable in the context of the ongoing controversy as to whether testosterone treatment should be limited to men with classical hypogonadism, or be considered for appropriately selected men with functional hypogonadism as well. The principal findings are in general agreement with existing literature reporting correlation between levels of testosterone, body mass index and constitutional symptoms. However, this has never been shown before in context of Indian population. The present study was carried out at Armed Forces Medical College and Command Hospital, Pune between October 2017 to August 2019.We studied to see if there is association between testosterone levels and BMI. In our study we found no statistical association as the p value was 0.26 (>0.05)

SUN-222 Testosterone Treatment in Men with Classical vs. Functional Hypogonadism: A 9-Year Registry

Introduction and Objective Longterm data of Testosterone (T) substitution in hypogonadal men are scarce and clinical value of this treatment is especially debated in men with functional (so called “late-onset”) hypogonadism. A long-term registry comprising various groups of patients provides an efficient tool to approach this issue. Methods Registry data of max. 9 years comprising 650 patients with hypogonadism including 266 men with primary forms (mean age 34.0±11.7 years), 196 with secondary origin (mean age 31.9±12.0 years) and 188 with functional hypogonadism (mean age 42.3±11.3 years) all receiving uniform treatment using intramuscular T undecanoate (1000 mg). Results The registry contained 8358 time points with a subset of metabolic and safety parameters each. Serum T concentrations increased from 5.7±2.3 nmol/L to 19.4±2.8 nmol/L in men with classical hypogonadism and from 7.8±2.4 nmol/L to 19.2±3.1 nmol/L in men with functional hypogonadism (difference in delta T: p<0.0001). There was an initial difference in the distribution of body mass index (BMI): 35.6% of men with classical hypogonadism and 51.6% of men with functional hypogonadism were obese (BMI>30 kg/m2, p=0.0006). Changes over time using Kaplan-Meier models revealed fundamental differences in inter-individual effects: men with functional hypogonadism were more likely to lose 10% weight and 5% of waist circumference (WC) than men with classical hypogonadism (hazard ratio 1.3 [1.1-1.4], p=0.008 and hazard ratio 1.4 [1.3-1.5], p=0.001). There was no difference for increase in hematocrit. Changes in PSA levels were more likely to occur in functional hypogonadism (hazard ratio 1.3 [1.1-1.6], p=0.003). Significantly more pronounced effects of T substitution in functional hypogonadism could also be attributed to changes in parameters of lipid metabolism (levels of total cholesterol, triglycerides, LDL- and HDL-cholesterol and glucose metabolism). Stepwise multiple Cox regression models could attribute these differences to the initial higher values in BMI, WC, lipids, glucose and age found in functional hypogonadism. The condition as such rather attenuated the effects of testosterone treatment compared to those seen in classical forms of hypogonadism, due to the lower increase of testosterone concentrations during treatment. Conclusions Major new findings regarding effects and safety of T substitution in different groups of hypogonadal men are provided. Effects on factors influencing cardiovascular health are modulated by diagnosis and age. Patients with functional hypogonadism seem to benefit to a larger extent from T substitution, this being a function of their initially worse status in cardiovascular risk factors compared to men with classical forms of hypogonadism.

MP85-15 TESTOSTERONE TREATMENT IN MEN WITH CLASSICAL VS FUNCTIONAL HYPOGONADISM:RESULTS FROM A 9-YEAR-REGISTRY

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy II1 Apr 2018MP85-15 TESTOSTERONE TREATMENT IN MEN WITH CLASSICAL VS FUNCTIONAL HYPOGONADISM:RESULTS FROM A 9-YEAR-REGISTRY Michael Zitzmann, Eberhard Nieschlag, Abdul Traish, and Sabine Kliesch Michael ZitzmannMichael Zitzmann More articles by this author , Eberhard NieschlagEberhard Nieschlag More articles by this author , Abdul TraishAbdul Traish More articles by this author , and Sabine KlieschSabine Kliesch More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2875AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There are limited data on long-term effects of Testosterone (T) therapy in hypogonadal men and clinical value of this treatment in men with functional (late-onset) hypogonadism remains hotly debated. A long-term registry comprising various groups of patients provides an efficient tool to approach this issue. METHODS Registry data of max. 9 years comprising 650 patients with hypogonadism including 266 men with primary (mean age 34.0 ± 11.7 years), 196 with secondary (mean age 31.9 ± 12.0 years) and 188 with functional hypogonadism (mean age 42.3 ± 11.3 years) all receiving uniform treatment using intramuscular T undecanoate (1000 mg). RESULTS The registry contained 8358 time points with a subset of metabolic and safety parameters. Serum T concentrations increased from 5.7 ± 2.3 nmol/L to 19.4 ± 2.8 nmol/L in men with classical hypogonadism and from 7.8 ± 2.4 nmol/L to 19.2 ± 3.1 nmol/L in men with functional hypogonadism (difference in delta T: p<0.0001). There was an initial difference in the distribution of body mass index (BMI): 35.6% of men with classical hypogonadism and 51.6% of men with functional hypogonadism were obese (BMI>30 kg/m2, p=0.0006).Changes over time using Kaplan-Meier models revealed fundamental differences in inter-individual effects: men with functional hypogonadism were more likely to lose 10% weight and 5% of waist circumference (WC) than men with classical hypogonadism (hazard ratio 1.3 [1.1-1.4], p=0.008 and hazard ratio 1.4 [1.3-1.5], p=0.001). There was no difference for increase in hematocrit. Changes in PSA levels were more likely to occur in functional hypogonadism (hazard ratio 1.3 [1.1-1.6], p=0.003). Significantly more pronounced effects of T therapy in functional hypogonadism could also be attributed to changes in parameters of lipid (levels of total cholesterol, triglycerides, LDL- and HDL-cholesterol) and glucose metabolism. Stepwise multiple Cox regression models could attribute these differences to the initial higher values in BMI, WC, lipids, glucose and age found in functional hypogonadism. The condition as such rather attenuated the effects of T therapy compared to those seen in classical hypogonadism, due to the lower increase of T concentrations during treatment. CONCLUSIONS This study provided major new findings regarding effects and safety of T therapy in different groups of hypogonadal men. Effects on factors influencing cardiovascular health are modulated by diagnosis and age. Patients with functional hypogonadism may experience greater benefits from T therapy; this being a function of their initially worse status in cardiovascular risk factors compared to men with classical forms of hypogonadism. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1174-e1175 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Michael Zitzmann More articles by this author Eberhard Nieschlag More articles by this author Abdul Traish More articles by this author Sabine Kliesch More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Have the Testosterone Trials demonstrated the effectiveness of testosterone therapy in older men without classical hypogonadism?

Have the Testosterone Trials demonstrated the effectiveness of testosterone therapy in older men without classical hypogonadism?

Demographic and Clinical Correlates of Patient-Reported Improvement in Sex Drive, Erectile Function, and Energy With Testosterone Solution 2%

IntroductionEvidence from well-designed studies documenting the benefit of testosterone replacement therapy as a function of patient demographic and clinical characteristics is lacking. AimTo determine demographic and clinical predictors of treatment outcomes in hypogonadal men with low sex drive, low energy, and/or erectile dysfunction. MethodsPost hoc analysis of a randomized, multicenter, double-blinded, placebo-controlled, 16-week study of 715 hypogonadal men (mean age = 55.3 years, age range = 19–92 years) presenting with low sex drive and/or low energy who received placebo or testosterone solution 2% for 12 weeks. Main Outcomes and MeasuresTwo levels defined patient-reported improvement (PRI) in sex drive or energy: level 1 was at least “a little better” and level 2 was at least “much better” in energy or sex drive on the Patient Global Impression of Improvement at study end point. PRI in erectile function was stratified by erectile dysfunction severity at baseline as measured by the erectile function domain of the International Index for Erectile Function: mild at baseline (change of 2), moderate at baseline (change of 5), and severe at baseline (change of 7). Associations of demographic and clinical characteristics with PRI were calculated with stepwise forward multiple logistic regression analysis. Odds ratios represented the likelihood of PRI in symptoms among variable categories. ResultsHigher levels of end-point testosterone were associated with higher rates of PRI (at levels 1 and 2) in sex drive and energy (P < .001 for the two comparisons). Lower baseline testosterone levels were associated with higher rates of level 1 PRI in sex drive (P = .028); and classic hypogonadism (vs non-classic hypogonadism) was associated with higher rates of level 2 PRI in sex drive (P = .005) and energy (P = .006). ConclusionWhen assessing the potential for improvements in men with testosterone deficiency using patient-reported outcome questionnaires, possible predictors of treatment outcomes to consider include the etiology of hypogonadism and testosterone levels (baseline and end point).

Hypotestosteronaemia in the aging male: should we treat it?

The term male hypogonadism is defined as the failure to maintain physiological concentrations of testosterone, a physiological quantity of sperm or the combination of both. Aetiologically, androgen deficiency can originate from the testes (primary hypogonadism) or from the hypothalamic-pituitary regulation of the testicular function (secondary hypogonadism). The causes of hypogonadism are very diverse and may be genetically determined (e.g. Klinefelter's syndrome) or acquired (tumours, infections, haemochromatosis). Classical hypogonadism linked to an underlying disease, such as a pituitary tumour, is a distinct indication for androgen substitution. But how about the aging male? It is known that there is a highly variable age-related decline in testosterone levels; whether this represents a variation of normality or has a true disease value requiring therapy has been disputed over more than a decade. The key questions surrounding this debate concern not only the age-dependent threshold for serum testosterone but, more importantly, the risks and benefits of testosterone replacement therapy in the aging male. We searched the literature for randomised controlled trials of testosterone administration in aging males with a size of at least 100 patients and a follow-up of at least 6 months, and identified eight studies. These studies mostly tried to evaluate the effect of testosterone on bone density, muscle strength and body composition, rather than clinically meaningful endpoints. Moreover, these trials have provided evidence for relevant cardiovascular adverse events in elderly men. This supports the need for further studies to define the treatment threshold for testosterone levels in the aging male, as well as with regard to the long-term risks and relevant benefits of testosterone therapy in this population. Until we have more solid data in aging males, testing for testosterone deficiency and testosterone replacement should remain reserved for patients with predisposing conditions, symptoms and signs of bona fide hypogonadism.

Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials.

The effects of testosterone treatment on glucose metabolism and other outcomes in men with type 2 diabetes (T2D) and/or the metabolic syndrome are controversial. To perform a systematic review and meta-analysis of placebo-controlled double-blind randomized controlled clinical trials (RCT) of testosterone treatment in men with T2D and/or the metabolic syndrome. A systematic search of RCTs was conducted using Medline, Embase and the Cochrane Register of controlled trials from inception to July 2014 followed by a manual review of the literature. Eligible studies were published placebo-controlled double-blind RCTs published in English. Two reviewers independently selected studies, determined study quality and extracted outcome and descriptive data. Of the 112 identified studies, seven RCTs including 833 men were eligible for the meta-analysis. In studies using a simple linear equation to calculate the homeostatic model assessment of insulin resistance (HOMA1), testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference (MD) -1·58 [-2·25, -0·91], P < 0·001. The treatment effect was nonsignificant for RCTs using a more stringent computer-based equation (HOMA2), MD -0·19 [-0·86, 0·49], P = 0·58). Testosterone treatment did not improve glycaemic (HbA1c) control, MD -0·15 [-0·39, 0·10], P = 0·25, or constitutional symptoms, Aging Male Symptom score, MD -2·49 [-5·81, 0·83], P = 0·14). This meta-analysis does not support the routine use of testosterone treatment in men with T2D and/or the metabolic syndrome without classical hypogonadism. Additional studies are needed to determine whether hormonal interventions are warranted in selected men with T2D and/or the metabolic syndrome.

Testosterone level in men with type2 diabetes mellitus and related metabolic effects: A review of current evidence.

A significant proportion of patients with type 2 diabetes mellitus have a low testosterone level relative to reference ranges based on healthy young men. Only a small number of these patients suffer from classical hypogonadism as a result of recognizable hypothalamic–pituitary–gonadal axis pathology. The cut-off value of the serum testosterone level in men without obvious hypothalamic–pituitary–gonadal axis pathology is controversial. It is unclear to what extent a low serum testosterone level causally leads to type 2 diabetes and/or the metabolic syndrome. From a theoretical standpoint, there can be complex interactions among the hypothalamic–pituitary–gonadal axis, body composition and insulin resistance, which can be further influenced by intrinsic and extrinsic factors to give rise to metabolic syndrome, glucose intolerance, and low-grade inflammation to increase the risk of cardiovascular disease. Although a low serum testosterone level frequently coexists with cardiometabolic risk factors and might serve as a biomarker, more studies are required to clarify the causal, mediating or modifying roles of low serum testosterone level in the development of adverse clinical outcomes. Currently, there are insufficient randomized clinical trial data to evaluate the effects of testosterone replacement therapy on meaningful clinical outcomes. The risk-to-benefit ratio of testosterone therapy in high-risk subjects, such as those with type 2 diabetes, also requires elucidation. The present article aims to review the current evidence on low serum testosterone levels in patients with type 2 diabetes, and its implications on cardiovascular risk factors, metabolic syndrome and adverse clinical outcomes.

Clinical practice patterns in the assessment and management of low testosterone in men: an international survey of endocrinologists.

To document current practices in the approach to low testosterone in older men. Given that recommendations are based on low-level evidence, we hypothesized that there would be a wide variability in clinical practice patterns. Members of all major endocrine and andrological societies were invited to participate in a Web-based survey of the diagnostic work-up and management of a hypothetical index case of a 61-year old overweight man presenting with symptoms suggestive of androgen deficiency, without evidence of hypothalamic-pituitary-gonadal (HPT) axis disease. Nine hundred and forty-three respondents (91·2% adult endocrinologists) from Northern America (63·7%), Europe (12·7%), Oceania (8·2%), Latin America and Caribbean (7·6%), and the Middle East, Asia, or Africa (7·8%) completed the survey. Response rates among participating societies ranged from 4·1-20·0%. There was a wide variability in clinical practice patterns, especially regarding biochemical diagnosis of androgen deficiency, exclusion of HPT axis pathology, and monitoring for prostate cancer. In a man with suggestive symptoms, 42·4% of participants would offer testosterone treatment below a serum total testosterone of 10·4 nmol/l (300 ng/dl). A total of 46·0% of participants were, over the last five years, 'less inclined' to prescribe testosterone to men with nonspecific symptoms and borderline testosterone levels, compared to 'no change' (29·3%) or 'more inclined' (24·7%), P < 0·001. This large-scale international survey shows a wide variability in the management of lowered testosterone in older men, with deviations from current clinical practice guidelines, and a temporal trend towards increasing reluctance to prescribe testosterone to men without classical hypogonadism. These findings highlight the need for better evidence to guide clinicians regarding testosterone therapy.

Late-onset hypogonadism: beyond testosterone.

Late-onset hypogonadism is defined as a combination of low testosterone (T) levels and typical symptoms and signs. A major area of uncertainty is whether T concentrations are always really sufficient to fully reflect Leydig cell (dys)function. Mild testicular alteration could be diagnosed only by additional biochemical markers, such as luteinizing hormone (LH) and 25-hydroxyvitamin D levels. These markers help in identifying the so-called “subclinical” hypogonadism (normal T, high LH levels). Patients with hypogonadism have frequently low levels of 25-hydroxyvitamin D due to impairment of the hydroxylating enzyme CYP2R1 in the testis. However, no data have been published dealing with the best treatment option (cholecalciferol – the Vitamin D precursor, or calcidiol - 25-hydroxylated form of Vitamin D) in these patients. We studied 66 patients with classic hypogonadism (total T [TT] <12 nmol l−1, LH ≥ 8 IU l−1) (n = 26) and subclinical hypogonadism (TT ≥ 12 nmol l−1, LH ≥ 8 IU l−1) (n = 40) and low 25-hydroxyvitamin D (<50 nmol l−1). Subjects received cholecalciferol (5000 IU per week) (n = 20) or calcidiol (4000 IU per week) (n = 46), and 25-hydroxyvitamin D and parathyroid hormone (PTH) were evaluated after 3 months of therapy. Supplementation with calcidiol significantly increased 25-hydroxyvitamin D and significantly decreased PTH levels in both groups of men with hypogonadism (primary, n = 16 and subclinical, n = 30), whereas supplementation with cholecalciferol did not modify their levels. This study shows for the first time that the administration of the 25-hydroxylated form of Vitamin D (calcidiol), and not the administration of the precursor cholecalciferol, restores 25-hydroxyvitamin D levels in subjects with hypogonadism.

Risks and benefits of testosterone therapy in older men

In young men (defined as age<50 years) with classic hypogonadism caused by known diseases of the hypothalamus, pituitary or testes, testosterone replacement therapy induces a number of beneficial effects, for example, the development of secondary sex characteristics, improvement and maintenance of sexual function, and increases in skeletal muscle mass and BMD. Moreover, testosterone treatment in this patient population is associated with a low frequency of adverse events. Circulating testosterone levels decline progressively with age, starting in the second and third decade of life, owing to defects at all levels of the hypothalamic-pituitary-testicular axis. In cohort studies, testosterone levels are associated weakly but consistently with muscle mass, strength, physical function, anaemia, BMD and bone quality, visceral adiposity, and with the risk of diabetes mellitus, coronary artery disease, falls, fractures and mortality. However, the clinical benefits and long-term risks of testosterone therapy--especially prostate-related and cardiovascular-related adverse events--have not been adequately assessed in large, randomized clinical trials involving older men (defined as age>65 years) with androgen deficiency. Therefore, a general policy of testosterone replacement in all older men with age-related decline in testosterone levels is not justified.

Relationship between testosterone deficiency and cardiovascular risk and mortality in adult men.

Classic male hypogonadism is associated with known adverse effects including decreased libido, erectile dysfunction, osteoporosis, and changes in body composition. Recently, we have come to appreciate that reduction in serum testosterone (T) levels resulting from aging or chronic disease or androgen deprivation therapy (ADT) have consequences similar to those seen in classic male hypogonadism which include increased fat mass, decreased lean body mass, decreased muscle strength, and sexual dysfunction. These data suggest that low T levels may represent a newly recognized cardiometabolic risk factor. Therefore, we carried out a careful review of the literature, focusing on major turning points of research and studies which gave more important and controversial contribution to the cardiovascular role of T. Observational studies and clinical trials investigating the relationship between T levels and cardiovascular disease and mortality were identified byMedline search. The results were synthesized, tabulated, and interpreted. The aim of this review is to discuss the association between low T levels and adverse metabolic profile such as insulin resistance, metabolic syndrome, and diabetes. We will also investigate the potential mechanisms by which male hypogonadism, especially age related or induced by ADT, may increase cardio-metabolic risk. Finally we will detail the emerging relationship between low T and mortality in men addressing also the reverse hypothesis that low T has a protective role by turning off T-dependent functions.

Testosterone for ‘late-onset hypogonadism’ in men?

Testosterone replacement therapy is indicated in men with a deficiency or absence of endogenous testosterone due to classical primary or secondary hypogonadism.1–8 Of note, however, some testosterone preparations are also...

Guideline for Male Testosterone Therapy: A European Perspective

Why are we suddenly assailed with a plethora of guidelines for testosterone (T) therapy in androgen deficiency (1– 3), a condition that has been managed with relative success and apparent patient satisfaction for nearly seven decades? Prescriptions for T in the United States have increased by 400% since 1999 (4), mainly in middle-aged men. Interestingly, this trend has not been duplicated in Europe [Intercontinental Marketing Services (IMS) Health Inc., New York, unpublished data] or Australasia (5). Has there been an epidemicofmalehypogonadisminNorthAmerica,ordoesthis reflect a substantial shift in approach to the diagnosis and treatment of androgen deficiency? The age-related decline in T (6) in an increasing elderly male population is the likely drive behind this trend, fueled by a number of factors specific to the United States. These include direct-to-patient pharmaceutical advertising, ready availability of reimbursement by health-care providers, willingness of patients to pay for prescriptions, prevalence of an antiageing ethos, and, most importantly, clinicians’ attitude in accepting perceived novel therapeutic opportunities. The use of T in men with chronic illnesses is still underappreciated and is unlikely to have contributed substantially to the prescribing increase. The latest of these practice guidelines from The Endocrine Society,likeothersbefore,areostensiblytargetedatallforms of T deficiency. However, it’s not difficult to see that the real target of these guidelines is the T decline associated with ageing, thereby implicating a proportion of older men (numerically a huge potential patient population) without pituitary-gonadaldiseaseaslikelyhypogonadalcandidatesfor T treatment. Thus, by being considered together with classical prepubertal and post-pubertal hypogonadism, the agerelated physiological decline in T has been conceived as a new syndrome of late-onset hypogonadism, given instant credibility by association and promulgated by proxy. The guideline therefore, intentionally or unintentionally, endorses the existence of a condition or syndrome on no evidence of high quality. In doing so, this commentator believes that a number of fundamental issues have been overlooked by the panel. Patients (usually of a younger age) with classical hypogonadism and ageing men with borderline low T are distinct clinical entities with divergent pathophysiology. Classical hypogonadism is caused by identifiable and irreversible pathologies leading to unequivocally low T levels whose clinical consequences predictably and safely respond to replacement therapy. T in ageing men declines to the borderline low range; this is a variable phenomenon, associated with obesity, co-morbidity, and medication use, and is potentially reversible and preventable. Causal relationships between symptoms/signs and T levels in older men are unproven, while the natural history and health outcomes of lower T are unknown. The clinical efficacy and risks of T intervention are unclear. Therefore, no convincing evidence currently exists toconfirmthatanandrogendeficiencystatepertainstoaging men. Thus, to consider the age-related hypotestosteronemia asaformoflate-onsethypogonadismandtorecommendthat the diagnosis and treatment are the same as for classical androgen deficiency is a gross oversimplification that may have potentially grave consequences for patients and providers. Guidelines should be based on evidence obtained from the relevant population to which they apply and not extrapolated from other sources through expediency.

Guideline for Male Testosterone Therapy: A Regulatory Perspective

Testosterone products are approved by the U.S. Food and Drug Administration (FDA) as replacement therapy for men with classical androgen deficiency (i.e. men with very low serum testosterone concentrations generally associated with specific medical disorders). We refer to this condition as classical hypogonadism. Many prescribers, however, advocate administration of testosterone to older men with an array of signs and symptoms, many of which may be related to normal aging, and a “low” serum testosterone concentration based on normative values for young men. For the purposes of this editorial, we refer to this condition by its most popularly accepted name, andropause (1). In 2002, the National Institute of Aging and the National Cancer Institute tasked the Institute of Medicine (IOM) to conduct a review of the current state of knowledge of the potential risks and benefits of testosterone therapy in older men and to make research recommendations regarding clinical trials (2). The IOM’s report was published in 2004 and concluded in its executive summary that “As the FDA-approved treatment for male hypogonadism, testosterone therapy has been found to be effective in ameliorating a number of symptoms in markedly hypogonadal males. Researchers have carefully explored the benefits of testosterone therapy in this population. However, there have been fewer studies, particularly placebo-controlled randomized trials, in the population of middle aged or older men who do not meet all the clinical diagnostic criteria for hypogonadism but who may have testosterone levels in the low range for young adult males and show one or more symptoms that are common to both aging and hypogonadism.” The IOM further concluded that “assessments of risks and benefits have been limited and uncertainties remain about the value of this therapy in older men.” In the June 2006 issue of this Journal, The Endocrine Society published its Clinical Practice Guideline on testosterone therapy in adult men (Clinical Guideline) (3). The authors appear to acknowledge the difference between classical hypogonadism in adult men and andropause because they address these distinct populations in separate sections of the Clinical Guideline. The authors recommend (section 2.3 of the Clinical Guideline) against a general clinical policy of offering testosterone therapy to all older men with low testosterone levels. This important statement, however, could be easily overlooked in the context of the overall document. The message of this statement also does not appear to be included in either the abstract or Patient Guide,* which are more likely to be read by providers and patients, respectively. In addition, the statement does not recommend against treating older men with low testosterone and symptoms of aging. The Clinical Guideline and its associated Patient Guide, we believe, obscure the distinction between classical hypogonadism and andropause and imply that the practice of treating men with andropause is efficacious and safe based on high-quality evidence. We agree with the authors’ assessments that the evidence regarding the strategies for diagnosis, treatment, and monitoring of older adult men with androgen deficiency syndromes is primarily supported by “very low quality evidence” (the lowest category on a four-level evidence grading scale). Notably, none of the evidence reviewed by the authors for the Clinical Guideline qualified as “high” or even “moderate quality.” It is, therefore, of great concern that The Endocrine Society offers primarily “strong recommendations” (and “suggestions”) regarding strategies for diagnosis, treatment, and monitoring of adult men who are undergoing testosterone therapy. The Clinical Guideline is described as an “evidence-based” document. This is defined as being based on strength of evidence rather than expert opinion (4). It does not appear, however, that the authors adhered to the method they selected to create the Clinical Guideline, the GRADE system (5). In this system, “recommendations should be formulated to reflect their strength—that is, the extent to which one can be confident that adherence will do more good than harm.” The GRADE working group further recommended, “in some instances it may not be appropriate to make a recommendation . . . when this is due to lack of good quality evidence . . . ” In cases of inadequate evidence, the working group recommended, as did the IOM, that specific additional research should be conducted. The abstract portion of the Clinical Guideline, which we believe is the portion most likely to be read and followed by treating physicians, is of greater concern. In this section, there is no mention at all of the poor quality of evidence that is the basis for the recommendations. Further, there are statements in the abstract that are modifications (and, thereby, potentially misleading) of recommendations in the body of the * Editor’s Note: The Patient Guide was not written by the Clinical Practice Guideline expert panel or peer-reviewed by The Journal of Clinical Endocrinology & Metabolism.