Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dl

Sexual Medicine Hypogonadal symptoms in young men are associated with a serum total testosterone threshold of 400 ng/dl Jason M. Scovell, Ranjith Ramasamy, Nathan Wilken, Jason R. Kovac and Larry I. Lipshultz Department of Urology, Baylor College of Medicine, Houston, TX, USA Objective To investigate the association between hypogonadal symptoms and serum total testosterone (TT) levels in young men (aged <40 years), in an attempt to determine whether there exists a clear-cut discriminatory threshold of TT below which hypogonadal symptoms become more prevalent. Patients and methods We retrospectively reviewed the charts of 352 men who presented to an outpatient Men s Health Clinic with chief complaint of low testosterone. Sexual, psychological and physical symptoms were evaluated using the Androgen deficiency in Aging Male (ADAM) questionnaire. Serum levels of TT were collected on the same day that men completed their ADAM questionnaires. We subsequently performed univariate (t-test, chi-square) and multivariate analyses (ordinal logistic regression) to evaluate factors that predicted a low TT level. Results The probability of hypogonadal symptoms increased at a serum TT level of 400 ng/dl. A cluster of symptoms: two psychological ( decreased energy, sadness ), and three physical ( decreased strength and endurance, decreased ability to play sports,and deterioration in work performance ) were most strongly associated with serum TT levels of <400 ng/dl. On multivariable analysis, only lack of energy predicted a TT level of <400 ng/dl. Conclusions Hypogonadal symptoms in men aged <40 years can be associated with a TT level of <400 ng/dl. Of the hypogonadal symptoms evaluated with the ADAM questionnaire, lack of energy appears to be the most important symptom that predicts a TT level of <400 ng/dl. Keywords libido, erectile dysfunction, ADAM, androgen deficiency, ageing male Introduction Hypogonadism is a clinical disorder consisting of a cluster of symptoms in the presence of low serum levels of total testosterone (TT), traditionally defined as a solitary threshold value of <300 ng/dl [1]. It is important to note that the TT threshold of 300 ng/dl was solely determined via panel consensus by the Endocrine Society [2] and based upon observational studies. Several other societies have suggested varying testosterone thresholds from 230 to 350 ng/dl [3]. The uniform application of a single serum threshold to define hypogonadism is not appropriate given that men can exhibit different symptoms at different serum TT levels [4]. Studies surveying population-based cohorts, e.g. the Men in Australia Telephone Survey (MATeS) [5], the Massachusetts Male Aging Study (MMAS) [6], or the European Male Ageing Study (EMAS) [7], provide useful information about the prevalence and incidence of hypogonadal symptoms in community dwelling men. However, these cohorts do not represent men who are actually seeking diagnosis and possible treatment. Consequently, it is of paramount importance to assess the symptom profiles of young patients to provide physicians with necessary tools for adequate management. Another important issue is that we are not certain what thresholds should be used for the definition of testosterone deficiency in men of any age. To our knowledge, this is the first study to evaluate the association between TT levels and hypogonadal symptoms in young men. Given the increasing prevalence of testosterone use among men of all ages [8], it is important to understand hypogonadal symptomatology in young men whose chief complaint is low testosterone. Therefore, we conducted a study in young men who presented with a chief complaint of either low testosterone or symptoms of hypogonadism. These men had never received testosterone supplementation therapy (TST) allowing us to specifically characterise the BJU Int 2015; 116: 142 146 wileyonlinelibrary.com BJU International ª 2014 BJU International doi:10.1111/bju.12970 Published by John Wiley & Sons Ltd. www.bjui.org

Hypogonadal symptoms in young men with TT <400 ng/dl unique symptom profiles associated with endogenously low serum TT and free testosterone levels. Patients and Methods After approval by the Institutional Review Board at Baylor College of Medicine (Houston, TX, USA), we evaluated 352 men (aged <40 years) seen consecutively between May 2013 and March 2014. These men presented with a chief complaint of low testosterone. Men using testosterone or other androgenic anabolic steroids (AAS) either at, or 6 months prior to, the time of the survey were excluded. We also excluded men who had presented with a primary diagnosis of infertility, Kleinfelter s syndrome, or secondary hypogonadism after appropriate assessment of history and endocrine evaluation with gonadotrophins. All men answered the Androgen Deficiency in the Aging Male (ADAM) questionnaire [9,10] and on the same day their testosterone levels were measured. The ADAM questionnaire consists of 10 Yes/No questions about symptoms, although not all of them necessarily indicate treatable symptoms of testosterone deficiency. All venous blood samples were obtained under standardised conditions before 10:00 h from fasting patients. Serum or plasma were separated at 800g. Serum TT and sex hormone binding globulin measurements were done using the radioimmunoassay Beckman Access II platform (Beckman Coulter, Fullerton, CA, USA). TT levels were fitted on a scatter plot to determine inflection points and threshold levels. Data was analysed using Microsoft Excel (Microsoft, Redmond, WA, USA) and SPSS (SPSS Inc., Chicago, IL, USA). Chi-squared tests were used to compare percentages and the Student s t-test was used to compare means. The Q Q test was used to verify that the variables were continuously distributed. Univariate and multivariable analysis was performed for age and the 10 symptoms identified on the ADAM questionnaire. Variables that were statistically significant on the univariate analysis were included in the multivariable analysis. All values are reported as the mean (SD) and t-tests were used to evaluate differences in means between groups. A P 0.05 was considered to indicate statistical significance. Results Of the 352 men aged <40 years, 210 men had a TT level of <300 ng/dl; 67 men had levels of 300 400 ng/dl; and 75 men had levels of >400 ng/dl. The mean (SD) age of the 352 men was 33.2 (4.2) years, and the mean (SD; range) TT level was 308 (170; 0.86 1537) ng/dl. Of the 10 hypogonadal symptoms, the probability of having five symptoms decreased (P < 0.05) in men with testosterone levels of >400 ng/dl (Table 1 and Fig. 1). These five symptoms included two psychological ( decreased energy, feeling sad ), and three physical ( decreased strength and endurance, decreased ability to play sports, and deterioration in work performance ). The probabilities of having the 10 hypogonadal symptoms that are part of the ADAM questionnaire, were similar in men with TT levels of <300 ng/dl and men whose levels were between 300 and 400 ng/dl (Fig. 1). On a univariate analysis, the presence of the same five symptoms predicted a testosterone level of <400 ng/dl. On multivariable analysis, only lack of energy predicted a testosterone level of <400 ng/dl. Of note, sexual symptoms (libido and erectile function) commonly thought to be associated with low testosterone did not identify men with testosterone levels of <400 ng/dl. In addition, none of the 10 symptoms evaluated predicted a testosterone level of <300 ng/dl. Discussion Hypogonadism is caused by insufficient concentrations of testosterone in the blood, resulting in symptoms of androgen deficiency. The reference range for most assays of TT is 300 800 ng/dl [11,12], meaning that only 2.5% of healthy men have concentrations of <300 ng/dl. A clinical threshold of 300 ng/dl is often cited in the literature as the biochemical definition of hypogonadism [2]. One argument for using 300 ng/dl as the threshold for diagnosing male hypogonadism is that there is a functional correlation with erectile dysfunction (ED). This relationship was determined in a study of 162 elderly (mean age 64.1 years) men with ED (mean duration 45.6 months), where a Korean group reported that hypogonadism (serum TT level of <300 ng/dl) was among the strongest independent predictors of a poor response to sildenafil25 100 mg for 8 weeks [13]. The threshold TT level below which signs and symptoms of androgen deficiency occur and testosterone replacement is beneficial is not known and varies among individuals depending on age and comorbid conditions, and among affected target organs. Therefore, there is no absolute value of the TT level below which clinical androgen deficiency or hypogonadism can be confirmed in all patients, especially in young men. Consequently, we evaluated the association between hypogonadal symptoms and serum TT levels in men who came to our outpatient men s health clinic with a chief complaint of low testosterone. We identified a serum TT level threshold of 400 ng/dl by evaluating probabilities of the different hypogonadal symptoms across various TT levels. Most previous studies have identified an association of low testosterone with sexual symptoms, such as poor erectile function [7,14,15] and low libido [16]. However, in our present study we found that physical and psychological symptoms were most often closely associated with testosterone levels of <400 ng/dl. Interestingly, only lack of energy remained statistically significant on a multivariable analysis. None of the sexual BJU International ª 2014 BJU International 143

Scovell et al. Table 1 Probability of hypogonadal symptoms on the basis of levels of serum total testosterone (TT). Category Question N TT <400 ng/dl, % n TT >400 ng/dl, % P Sexual Do you have decreased libido? 255 42 71 38 0.587 Are your erections less strong? 273 44 73 36 0.232 Psychological Have you noticed a decreased enjoyment in life? 272 31 73 22 0.148 Are you sad and/or grumpy? 269 31 73 18 0.028 Do you have a lack of energy? 265 55 74 32 <0.001 Physical Do you have a decrease in strength and or endurance? 269 46 73 30 0.023 Has there been a recent deterioration in your work performance? 273 24 75 12 <0.001 Are you falling asleep after dinner? 276 33 74 26 0.260 Have you noticed a recent deterioration in your ability to play sports? 272 31 71 15 0.008 Have you lost height? 274 4 73 1 0.470 Bolded significance values indicate P < 0.05. Fig. 1 Association between probability of hypogonadal symptoms and serum TT levels. P < 0.05 pairwise comparisons were performed between men with TT levels of >400 ng/dl (green), 300 400 ng/dl (red) and <300 ng/dl (blue). 60% 0 300 300 400 400 1600 Probability of Hypogonadal Symptom 50% 40% 30% 20% 10% 0% Do you have decreased libido? Do you have a lack of energy? Do you have a decrease in strength and or endurance? Have you noticed a decreased enjoyment in life? Are you sad and/or grumpy? Are your erections less strong? Question Has there been a recent deterioration in your work performance? Are you falling asleep after dinner? Have you Have you lost noticed a recent height? deterioration in your ability to play sports? symptoms evaluated (libido and poor erectile function) predicted a low TT level. A large general population of community dwelling men aged 40 79 years was evaluated in the EMAS [7]. The EMAS reported two important findings. First, sexual symptoms, such as ED and low libido, were most closely associated with low testosterone. Second, the TT threshold below which these sexual symptoms became more prevalent varied from 320 to 350 ng/dl. Although poor erectile function and low libido were among the most common symptoms seen in our present study, the presence of these symptoms did not predict TT levels of <400 ng/dl (Table 2). Although sexual symptoms may be a good indicator of low testosterone in community dwelling middle-aged, and elderly men, they remain a poor indicator for identifying low testosterone in men aged <40 years attending a men s health clinic. The cluster of symptoms that predict a low testosterone in young men suggests that appropriate age and population-based questions need to be asked before initiating hypogonadism treatment. In most men, serum TT concentrations of >300 ng/ml indicate that there is a low likelihood of clinically significant androgen deficiency. Threshold TT levels were calculated on the basis of symptoms for which the probability was significantly increased among men with a decreased TT level, as compared with men who had an increased level of TT. No thresholds were identified for sexual symptoms associated with TT. When evaluating prevalence of symptoms at the often-used TT threshold of 300 ng/dl, we did not find a significant difference between men. In our clinical experience, many patients with serum TT levels between 300 and 400 ng/dl, still report hypogonadal symptoms. Due to this discrepancy between standard practice and clinical experience, 144 BJU International ª 2014 BJU International

Hypogonadal symptoms in young men with TT <400 ng/dl Table 2 Univariate and multivariable analysis of hypogonadal symptoms predicting a serum TT level of <400 ng/dl. Only factors that were statistically significant (P < 0.05) on univariate analysis were included in the multivariable analysis. Analysis Odds ratio 95% CI P Univariate Age 1.01 0.95 1.07 0.807 Do you have decreased libido? 1.18 0.69 2.02 0.552 Do you have a lack of energy? 2.56 1.48 4.40 0.001 Do you have a decrease in strength or endurance? 1.95 1.12 3.40 0.018 Have you noticed a decreased enjoyment in life? 1.59 0.86 2.93 0.136 Are you sad and/or grumpy? 2.06 1.07 3.96 0.030 Are your erections less strong? 1.40 0.82 2.39 0.221 Has there been a recent deterioration in your work performance? 2.29 1.08 4.85 0.030 Are you falling asleep after dinner? 1.45 0.81 2.58 0.210 Have you noticed a recent deterioration in your ability to play sports? 2.48 1.24 4.95 0.010 Have you lost height? 2.73 0.34 21.66 0.343 Multivariable Do you have a lack of energy? 2.59 1.06 6.35 0.037 Do you have a decrease in strength or endurance? 0.64 0.25 1.61 0.341 Are you sad and/or grumpy? 1.03 0.42 2.52 0.954 Has there been a recent deterioration in your work performance? 0.94 0.37 2.38 0.889 Have you noticed a recent deterioration in your ability to play sports? 2.60 0.97 6.95 0.057 Bolded significance values indicate P < 0.05. we chose to investigate whether or not any hypogonadal symptoms predicted serum TT levels of <400 ng/dl in our present population. Our present findings support our clinical experience that many men with serum TT levels between 300 and 400 ng/dl can still present with hypogonadal symptoms. Other investigators have shown an association between energy and TT levels. In an age-matched cohort of young hypogonadal and euogonadal males, hypogonadal men reported greater fatigue (10 vs 7, P = 0.03) compared with their eugonadal counterparts [17]. A double-blind placebo control study has shown that hypogonadal males treated with TST report less fatigue (P = 0.03) [18]. Furthermore, in patients with obstructive sleep apnoea, which is commonly associated with fatigue, Bercea et al. [19] found in a case-control study that serum TT levels were the only independent predictors of physical fatigue (R 2 = 0.98, P = 0.033) and reduced activity (R 2 = 0.97, P = 0.002). Young men are less likely to have organic factors contributing to ED [20], and our present data suggests that the sexual symptoms often seen in elderly hypogonadal men are less important in diagnosing clinical hypogonadism in younger men. Our present study has both strengths and limitations. We minimised heterogeneity by surveying men as they were seen consecutively and by excluding men who had received AAS and TST in the previous 6 months. We used the ADAM questionnaire, which was originally validated in elderly men and was used to screen for adult-onset hypogonadism [21]. Despite poor specificity, ADAM remains one of the best-validated questionnaires for studying hypogonadal symptoms. We also recorded a single morning serum TT level for patients at the visit when they completed the ADAM questionnaire. While this provided a good record of the relationship between serum TT levels and hypogonadal symptoms, multiple evaluations of TT levels and symptoms could have yielded a more robust comparison. Our present observations should be extrapolated to the diagnosis of testosterone deficiency in patients with the caveat that a low TT level requires confirmation with repeated measurement. Furthermore, the documentation of low TT levels in symptomatic young men does not invariably imply that a low TT level is the only or foremost cause of their physical or psychological symptoms. A comprehensive general assessment is required to seek potential alternative explanations. Obviously, these data do not set the criteria for initiating testosterone replacement but give valuable guidance to the practicing physician about what threshold to use and what symptoms to evaluate in young hypogonadal men. In summary, among men aged <40 years of age visiting a Men s Health Clinic, lack of energy predicted a serum TT level of <400 ng/dl. As there were no differences in hypogonadal symptom probability at 300 ng/dl and presence of the symptoms did not predict a TT level of <300 ng/dl, we think a TT of 300 ng/dl should not be used to diagnose hypogonadism in young men. We propose the existence of unique hypogonadal symptoms that become increasingly prevalent in young men. Rather than using solitary, predefined levels of serum TT (i.e. <300 ng/dl) as thresholds for treatment, we recommend using a different threshold based on symptomatology. The notion that common and uniform concentrations of androgen levels can be applied to describe the increasing prevalence of testosterone-related symptoms in young men should be challenged on the basis of the conclusions from the present study. BJU International ª 2014 BJU International 145

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