2022 Volume 69 Issue 11 Pages 1303-1312
The Aging Males’ Symptoms (AMS) score, developed to screen for late-onset hypogonadism (LOH), contains 17 questions regarding mental, physical, and sexual parameters. In the Japanese guidelines, a free testosterone (FT) <8.5 pg/mL is recommended for testosterone treatment. However, previous studies have shown no correlation between total AMS scores and testosterone concentration. We aimed to develop a better questionnaire for the detection of testosterone deficiency in men, for the diagnosis of LOH. In 234 Japanese men, aged 40–64 years, we analyzed the relationships of AMS with serum total testosterone (TT), FT, calculated FT (cFT), and calculated bioavailable testosterone (cBT), and identified useful questions for the detection of testosterone deficiency. Four scores, a decrease in muscular strength, a decrease in ability to perform sexually or the frequency, a decrease in the number of morning erections, and a decrease in sexual desire/libido, were negatively associated with two or more of the above four testosterone parameters, and the sum of these four scores (named the selective score) correlated with TT and cFT, independent of age. Statistical analysis revealed an association between insulin resistance and testosterone deficiency, and a higher selective score in smokers than non-smokers. Cubic function model analysis and logistic regression analysis revealed that selective scores ≥10 corresponded with the testosterone concentrations recommended for the diagnosis of LOH, including FT <8.5 pg/mL, independent of age, insulin resistance, and smoking. Thus, the selective score represents a simple and useful means for screening of testosterone deficiency in Japanese men, as an indicator of LOH.
SINCE THE INTERNATIONAL SOCIETY for the Study of the Aging Male was founded in 1998, various groups have tried to establish criteria for the diagnosis of late-onset hypogonadism (LOH) and its therapy. In 1999, the Aging males’ symptoms (AMS) score was developed as a symptom profiling approach in Germany [1]. In the AMS, the severity of the symptoms of LOH is evaluated not only using the total score derived from all 17 questions, which assess parameters on a five-point scale, but also from three scores for the psychological, physical, and sexual sub-scales. The AMS is now well accepted internationally.
The AMS is thought to be a useful means of assessing the effects of testosterone (T) replacement therapy on quality of life [2]. However, previous studies, including our own, have found no correlation between the AMS and serum T concentration [2-4]. Furthermore, the AMS scale was shown not to be an effective means of identifying T deficiency, because of its low specificity [5]. Two other screening questionnaires have also been developed: the Androgen Deficiency-Aging Male (ADAM) scale, by Morley et al. [6] and Screener, by Smith et al. [7]. However, these questionnaires were also shown not to be effective means of identifying T deficiency, because the scores were not associated with the serum concentrations of total testosterone (TT), free testosterone (FT), or bioavailable T [5, 8]. Indeed, ADAM had a specificity of only 21.6% for the identification of aging men with low free T concentrations [9].
Only the psychological symptom score of the AMS scores was reported to be associated with serum T concentration in men aged 45–60 years who were employed as manual workers by the Vienna Municipality [10]. In our previous study, no significant association was identified between total AMS score and T concentration, and only the sexual subscale scores were significantly inversely associated with FT or calculated bioavailable testosterone (cBT) [4].
Several T concentrations have been recommended for use in the diagnosis and treatment of LOH. Internationally, the European Association of Urology (EAU) have recommended newly last year, that patients with serum TT concentrations <3.5 ng/mL (12.0 nmol/L) and/or calculated free testosterone (cFT) concentrations <65 pg/mL (225 nmol/L) are diagnostic of LOH, because they might benefit from T administration [11]. In contrast, the American Urological Association (AUA) suggested that threshold values of TT <3.0 ng/mL should be used for LOH [12]. In Japan, FT <8.5 pg/mL is recommended by the Japanese Urological Association and The Japanese Society of Men’s Health to be the threshold below which T replacement should be considered [13]. However, there has been little investigation regarding which questionnaire best reflects T deficiency in Japanese men with LOH. Therefore, we aimed to develop an effective questionnaire for the purpose of identifying T deficiency in Japanese men, for use in the diagnosis of LOH.
The 234 male participants in this study (Table 1) were the same cohort reported previously [4] who visited the Department of Preventive Medicine at Iizuka Hospital for a health examination. The Institutional Review Boards of Fukuoka University Hospital and Iizuka Hospital approved the study (approval numbers 11-5-08 and 11-21, respectively). All the participants provided their written informed consent. Of the 241 participants in the previous study, seven aged ≥65 years were excluded, because the present study was of middle-aged men.
| Age (years) | 51.8 ± 6.2 | Severity of symptoms (AMS total scores) | n (%) |
| BMI (kg/m2 ) | 23.9 ± 2.9 | normal (17–26) | 91 (38.9) |
| Waist C (cm) | 86.8 ± 8.1 | mild (27–36) | 80 (34.2) |
| moderately severe (37–49) | 48 (20.5) | ||
| Hb (g/dL) | 14.8 ± 0.97 | severe (≥50) | 15 (6.4) |
| Hct (%) | 44.4 ± 3.1 | ||
| Alb (g/dL) | 4.3 ± 0.2 | Current smoking habit | |
| HDL-C (mg/dL) | 54.5 ± 11.4 | no | 153/230 (66.5) |
| LDL-C (mg/dL) | 117.3 ± 28.3 | yes | 77/230 (33.5) |
| TG (mg/dL) | 126.8 ± 67.5 | ||
| FPG (mg/dL) | 99.8 ± 11.8 | Drinking habit | |
| HbA1c (%) | 5.3 ± 0.4 | no | 27/229 (11.8) |
| F-IRI (μIU/mL) | 6.6 ± 4.1 | sometimes | 65/229 (28.4) |
| HOMA-IR | 1.67 ± 1.20 | almost every day | 137/229 (59.8) |
| TT (ng/mL) | 4.92 ± 1.62 | ||
| FT (pg/mL) | 10.61 ± 3.47 | ||
| cFT (pg/mL) | 82.18 ± 24.13 | ||
| cBT (ng/mL) | 1.91 ± 0.55 |
Data are shown as mean ± SD or number (%). BMI, body mass index; Waist C, waist circumference; Hb, hemoglobin; Hct, hematocrit; Alb, albumin; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TG, triglyceride; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; F-IRI, fasting insulin; HOMA-IR, homeostatic model assessment of insulin resistance; TT, total testosterone; FT, free testosterone; cFT, calculated free testosterone; cBT, calculated bioavailable testosterone.
As described previously [14], participants who were taking drugs for the treatment of diabetes mellitus or hyperlipidemia were excluded, because the previous study focused on the relationship between testosterone concentration and metabolic syndrome. Of the 234 participants in the present study, four had glycated hemoglobin (HbA1c) ≥6.5%, 47 had low-density lipoprotein-cholesterol (LDL-C) ≥140 mg/dL, 66 had triglyceride (TG) ≥150 mg/dL, and 41 were taking antihypertensive drugs. The questionnaire used in the present study was based on the self-reporting of smoking habits, alcohol consumption habits, comorbidities, and medication. The smoking and alcohol consumption habits of the participants are summarized in Table 1, except for a few who gave no answer. There were no self-reported instances of depression, lower urinary tract symptoms, or the use of cGMP-specific type 5 phosphodiesterase (PDE5) inhibitors, which might have affected T concentration and/or LOH symptoms, among the participants.
The hematological and biochemical data, including albumin, high density lipoprotein cholesterol (HDL-C), LDL-C, TG, fasting plasma glucose (FPG), HbA1c, fasting immunoreactive insulin (F-IRI), and homeostatic model assessment of insulin resistance (HOMA-IR), were collected during the previous study [14].
The self-rated scores already obtained from the AMS questionnaires of the 234 participants [4, 14] were analyzed in the present study. The AMS questionnaire contained 17 symptom-based questions on three subscales, comprising five mental (Nos. 6–8, 11, and 13), seven physical (Nos. 1–5, 9, and 10), and five sexual (Nos. 12 and 14–17) questions (Table 2). The responses to each question were assigned a rating of 1–5 (from none to extremely severe). The sum of the scores for the 17 items provided a total score, and the sums of the sub-scores for the mental, physical, and sexual questions were also calculated.
| p for trend | |||||
|---|---|---|---|---|---|
| Age | TT | FT | cFT | cBT | |
| 1. Decline in your feeling of general well-being | 0.666 | 0.072 | 0.875 | 0.480 | 0.481 |
| 2. Joint pain and muscular ache | 0.121 | 0.147 | 0.026 | 0.086 | 0.077 |
| 3. Excessive sweating | 0.628 | 0.057 | 0.776 | 0.263 | 0.295 |
| 4. Sleep problems | 0.019 | 0.301 | 0.513 | 0.387 | 0.429 |
| 5. Increased need for sleep, often feeling tired | 0.830 | 0.008 | 0.055 | 0.054 | 0.080 |
| 6. Irritability | 0.559 | 0.689 | 0.827 | 0.695 | 0.916 |
| 7. Nervousness | 0.788 | 0.636 | 0.984 | 0.742 | 0.665 |
| 8. Anxiety | 0.463 | 0.325 | 0.817 | 0.725 | 0.645 |
| 9. Physical exhaustion / lacking vitality | 0.814 | 0.947 | 0.860 | 0.750 | 0.825 |
| 10. Decrease in muscular strength | 0.097 | 0.073 | 0.094 | 0.040 | 0.040 |
| 11. Depressive mood | 0.649 | 0.763 | 0.756 | 0.820 | 0.856 |
| 12. Feeling that you have passed your peak | 0.043 | 0.328 | 0.165 | 0.274 | 0.237 |
| 13. Feeling burnt out, having hit rock-bottom | 0.088 | 0.119 | 0.053 | 0.251 | 0.199 |
| 14. Decrease in beard growth | 0.037 | 0.177 | 0.036 | 0.124 | 0.077 |
| 15. Decrease in the ability to perform sexually or its frequency | <0.001 | 0.003 | 0.015 | <0.001 | <0.001 |
| 16. Decrease in the number of morning erections | <0.001 | 0.053 | 0.022 | 0.041 | 0.026 |
| 17. Decrease in sexual desire/libido | <0.001 | 0.025 | <0.001 | 0.006 | 0.003 |
Data are presented as p values, obtained using the Jonckheere-Terpstra analysis. TT, total testosterone; FT, free testosterone; cFT, calculated free testosterone; cBT, calculated bioavailable testosterone. The AMS score consists of three components, the mental, physical, and sexual sub-scales. Question numbers 6–8, 11, and 13 evaluate mental state, question numbers 1–5, 9, and 10 evaluate physical state, and question numbers 12 and 14–17 evaluate sexual state.
The serum concentrations of TT, FT, cFT, and cBT were measured in our previous study [4]. FT values were missing for two participants. cFT and cBT were calculated using the Free & Bioavailable Testosterone Calculator on the basis of the measured TT and SHBG concentrations, as previously described [14]. These data were used in the present study to clarify the relationships between these parameters and the AMS scores.
We assessed the relationships between the score for each item and the serum concentrations of TT, FT, cFT, and cBT. We selected several items that significantly correlated with two or more T parameters, and named the sum of the scores for these items the ‘selective score’. We also assessed the relationships of the total scores, three the sub-scores (mental, physical, and sexual), and the selective score with the serum concentrations of TT, FT, cFT, and cBT using linear regression, and the relationships between them when adjusted for age. Then, we investigated the cut-off values of the selective score considering the relationships with the TT, FT, and cFT concentrations recommended for use in the diagnosis of LOH, and the effect of the metabolic factors.
Statistical analysisNormally distributed data are expressed as the mean ± standard deviation. The Jonckheere-Terpstra analysis was performed to investigate the relationships of each AMS 17 item with the T parameters or metabolic parameters, and to assess the relationships of alcohol intake with the selective score and T concentrations. We evaluated the effect of smoking on the selective scores and T parameters using Student’s t-test. The relationships of AMS total score, component sub-scores, and the selective score with T parameters and metabolic parameters were assessed using simple regression analysis. For the relationship between the selective score and each T parameter, the more appropriate model (the cubic function, rather than the linear regression model) was adopted and the most appropriate cut-off value of selective score for the screening for LOH was identified. We also performed logistic regression analysis to determine whether the T parameters contributed to the selective score, after adjustment for age, smoking habits, and key metabolic parameters. Statistical analyses were performed using SPSS Statistics (v. 26.0; IBM Corp., Armonk, NY, USA) and p < 0.05 was considered to denote significance.
The characteristics of the 234 men aged 40–64 years, including their age, body mass index (BMI), waist circumference (Waist C), hematological data, biochemical data (albumin, HDL-C, LDL-C, TG, FPG, HbA1c, F-IRI, and HOMA-IR), T concentrations, and AMS scores are presented in Table 1. The mean AMS score was 31.6 ± 10.1. There were 91 (38.9 %), 80 (34.2 %), 48 (20.5%), and 15 (6.4 %) men with normal (17–26), mild (27–36), moderately severe (37–49), and severe (≥50) AMS scores, respectively. Even though all of the participants underwent a regular health examination alone, 61.1% of the participants displayed abnormal score (total AMS ≥27). The relationships among the various T parameters are shown in Supplementary Table 1. As expected, TT, FT, cFT, and cBT significantly correlated with each other.
Of these men, 70/232 (30.2%) had a FT concentration of <8.5 pg/mL, which has been proposed to be an indication for T treatment of LOH in Japan [13]. When using the EAU recommendation for LOH, namely TT concentration <3.50 ng/mL and/or cFT levels <65 pg/mL [11], 69 participants were identified to have clinical LOH (29.5%). When using the AUA criteria for LOH [12], namely TT <3.0 ng/mL, there were 18 men with LOH (7.7%).
Next, we assessed the relationships of each of the 17 AMS scores with age and the serum concentrations of TT, FT, cFT, and cBT (Table 2). Four questions, namely a decrease in muscular strength (No. 10), a decrease in the ability to perform sexually or its frequency (No. 15), a decrease in the number of morning erections (No. 16), and a decrease in sexual desire/libido (No. 17) were inversely associated with the serum concentrations of two or more of TT, FT, cFT, and cBT. We named the sum of these four scores, which reflects T deficiency, the ‘selective score’.
We then compared the relationships of the total AMS score, scores for the three components (mental, physical, and sexual), and the ‘selective score’ with age and the serum T concentrations (Table 3). FT, cFT, and cBT significantly inversely correlated with age. The physical score correlated only with TT concentration. The sexual score and the selective score significantly correlated with age (r = 0.271 and 0.277), TT concentration (r = –0.132 and –0,158), FT (r = –0.171 and –0.173), cFT (r = –0.185 and –0.212), and cBT (r = –0.201 and –0.228). There were no significant relationships between the other two scores (mental or AMS total score) and the T parameters.
| Age | TT | FT | cFT | cBT | |
|---|---|---|---|---|---|
| Age | 1 | –0.118 | –0.371** | –0.346** | –0.379** |
| Mental score | 0.021 | –0.036 | 0.0003 | –0.017 | –0.019 |
| Physical score | 0.077 | –0.131* | –0.067 | –0.094 | –0.103 |
| Sexual score | 0.271** | –0.132* | –0.171** | –0.185** | –0.201** |
| AMS total score | 0.138* | –0.118 | –0.091 | –0.114 | –0.125 |
| Selective score (4 items) | 0.277** | –0.158* | –0.173** | –0.212** | –0.228** |
Correlation coefficients were calculated by linear regression analysis using the Pearson product-moment correlation coefficient method. Selective score, the sum of the scores for Nos. 10, 15, 16, and 17; TT, total testosterone; FT, free testosterone; cFT, calculated free testosterone; cBT, calculated bioavailable testosterone. * p < 0.05, ** p < 0.01.
After adjustment for age, there were no significant relationships of the AMS sexual score or the sum of the three sexual items (Nos. 15–17) in the selective score with any of the T parameters. However, the selective score significantly correlated with TT (β = –0.127, p = 0.045) and cBT (β = –0.143, p = 0.035), and the correlation with cFT was borderline significant (β = –0.132, p = 0.050). Therefore, the selective score seemed to be superior to the AMS sexual score for the identification of low T status.
Various testosterone parameters and the AMS score have been shown to be associated with metabolic factors [4, 14]. With respect to the relationships of the 17 individual AMS items with metabolic factors, age was associated with item No.4 (physical component), No. 12, and Nos. 14–17 items (all sexual components). Waist C was associated with Nos. 15 and 16 (sexual components). F-IRI and HOMA-IR were associated with No. 1 (physical component) and Nos. 12, 16, and 17 (sexual components). The score for No. 10 (physical component), which is included in the selective score, was not associated with any of the metabolic parameters (Table 4).
| p for trend | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | BMI | Waist C | Hb | Hct | Alb | HDL-C | LDL-C | TG | FPG | HbA1c | F-IRI | HOMA-IR | |
| 1. Decline in your feeling of general well-being | 0.666 | 0.282 | 0.561 | 0.220 | 0.136 | 0.673 | 0.191 | 0.981 | 0.315 | 0.150 | 0.296 | 0.047 | 0.036 |
| 2. Joint pain and muscular ache | 0.121 | 0.302 | 0.141 | 0.089 | 0.483 | 0.699 | 0.934 | 0.491 | 0.695 | 0.609 | 0.142 | 0.942 | 0.912 |
| 3. Excessive sweating | 0.628 | 0.243 | 0.078 | 0.417 | 0.309 | 0.858 | 0.512 | 0.783 | 0.019 | 0.653 | 0.802 | 0.271 | 0.205 |
| 4. Sleep problems | 0.019 | 0.772 | 0.799 | 0.197 | 0.283 | 0.302 | 0.983 | 0.127 | 0.672 | 0.049 | 0.056 | 0.211 | 0.140 |
| 5. Increased need for sleep, often feeling tired | 0.830 | 0.696 | 0.753 | 0.287 | 0.380 | 0.650 | 0.907 | 0.283 | 0.904 | 0.677 | 0.808 | 0.794 | 0.777 |
| 6. Irritability | 0.559 | 0.971 | 0.825 | 0.379 | 0.678 | 0.373 | 0.854 | 0.520 | 0.566 | 0.364 | 0.197 | 0.317 | 0.301 |
| 7. Nervousness | 0.788 | 0.833 | 0.542 | 0.543 | 0.746 | 0.854 | 0.863 | 0.170 | 0.103 | 0.198 | 0.011 | 0.571 | 0.476 |
| 8. Anxiety | 0.463 | 0.821 | 0.915 | 0.630 | 0.559 | 0.739 | 0.281 | 0.350 | 0.684 | 0.160 | 0.997 | 0.120 | 0.097 |
| 9. Physical exhaustion / lacking vitality | 0.814 | 0.954 | 0.601 | 0.094 | 0.059 | 0.397 | 0.807 | 0.845 | 0.817 | 0.806 | 0.337 | 0.762 | 0.844 |
| 10. Decrease in muscular strength | 0.097 | 0.757 | 0.108 | 0.538 | 0.684 | 0.669 | 0.730 | 0.852 | 0.223 | 0.149 | 0.811 | 0.375 | 0.544 |
| 11. Depressive mood | 0.649 | 0.266 | 0.375 | 0.182 | 0.284 | 0.419 | 0.973 | 0.624 | 0.384 | 0.503 | 0.459 | 0.644 | 0.562 |
| 12. Feeling that you have passed your peak | 0.043 | 0.909 | 0.272 | 0.256 | 0.366 | 0.570 | 0.500 | 0.670 | 0.985 | 0.054 | 0.080 | 0.030 | 0.018 |
| 13. Feeling burnt out, having hit rock-bottom | 0.088 | 0.260 | 0.271 | 0.192 | 0.277 | 0.183 | 0.202 | 0.796 | 0.833 | 0.471 | 0.131 | 0.162 | 0.144 |
| 14. Decrease in beard growth | 0.037 | 0.345 | 0.284 | 0.421 | 0.332 | 0.271 | 0.123 | 0.038 | 0.410 | 0.988 | 0.141 | 0.335 | 0.322 |
| 15. Decrease in ability/frequency to perform sexually | <0.001 | 0.190 | 0.032 | 0.052 | 0.031 | 0.309 | 0.259 | 0.609 | 0.190 | 0.960 | 0.137 | 0.098 | 0.093 |
| 16. Decrease in the number of morning erections | <0.001 | 0.054 | 0.007 | 0.710 | 0.710 | 0.165 | 0.497 | 0.791 | 0.200 | 0.511 | 0.229 | 0.018 | 0.016 |
| 17. Decrease in sexual desire/libido | <0.001 | 0.288 | 0.196 | 0.316 | 0.206 | 0.338 | 0.048 | 0.712 | 0.264 | 0.709 | 0.018 | 0.041 | 0.035 |
Data are presented as p values, obtained using Jonckheere-Terpstra analysis. Bold data mean that p value is less than 0.05. BMI, body mass index; Waist C, waist circumference; Hb, hemoglobin; Hct, hematocrit; Alb, albumin; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TG, triglyceride; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; F-IRI, fasting insulin; HOMA-IR, homeostatic model assessment of insulin resistance. The AMS score consisted of three components: mental, physical, and sexual. Question numbers 6–8, 11, and 13 evaluate mental state, question numbers 1–5, 9, and 10 evaluate physical state, and question numbers 12 and 14–17 evaluate sexual state.
Regarding the relationships between the scores for the three AMS components, the total AMS score, or the selective score and hematological or metabolic factors, the three component scores and AMS total score positively correlated with F-IRI and HOMA-IR, as shown previously [4]; and the selective score correlated with Waist C, F-IRI, and HOMA-IR (r = 0.135, 0.136, and 0.145, respectively; p < 0.05) (Supplementary Table 2). In contrast, all of TT, FT, cFT, and cBT negatively correlated with BMI (r = –0.336, –0.242, –0.199 and –0.20, respectively; p < 0.01), Waist C (r = –0.338, –0.238, –0.239, and –0.241; p < 0.01), F-IRI (r = –0.295, –0.171, –0.223, and –0.206; p < 0.01), and HOMA-IR (r = –0.290, –0.186, –0.221, and –0.207; p < 0.01), as shown previously [14]. Taken together, these results suggest that there is a close relationship between insulin resistance and disturbed sexual function, which is probably caused by relative T deficiency.
For the selective score, higher coefficients of determination for TT, FT, cFT, and cBT were obtained using the cubic function model (r2 = 0.047, 0.083, 0.078, and 0.090, respectively; p < 0.05) (Fig. 1) than using the linear function model (r2 = 0.025, 0.030, 0.045, and 0.052, respectively). Therefore, we used the cubic function model to identify the most appropriate cut-off values of the selective score for use in the diagnosis of LOH, corresponding to an FT of 8.5 pg/mL in Japan, a TT of 3.5 ng/mL, and/or a cFT of 65 pg/mL, as used by the EAU [11], and a TT of 3.0 ng/mL, as used by the AUA [12]. The selective scores corresponding to TT concentrations of 3.5 ng/mL or 3.0 ng/mL, a FT of 8.5 pg/mL, and a cFT of 65 pg/mL were 9.42 or 9.94, 9.10, and 9.19, respectively (Fig. 1A–C). These values seemed to be at the transition from a steep negative slope to a smooth slope on the graphs of cubic function. Therefore, we considered a selective score of 9 or 10 points to be useful in the screening for or diagnosis of LOH in these Japanese men.
Graphs of cubic function analysis showing the correlations of our proposed selective scores with the levels of TT (A), FT (B), cFT (C), and cBT (D)
TT, total testosterone; FT, free testosterone; cFT, calculated free testosterone; cBT, calculated bioavailable testosterone
Next, we determined whether the various T concentrations used for the diagnosis of LOH were associated with a selective score of ≥9 or 10 points using logistic regression analysis, after adjustment for age, Waist C, and HOMA-IR, which correlated with several T parameters and the selective score. When we assessed the effect of smoking or alcohol consumption on the T parameters and the selective score, none of the T concentrations differed between participants who did or did not smoke (Student’s t-test). However, selective score of the smoking group (n = 77) was significantly higher than that of the non-smoking group (n = 153) (9.47 ± 3.37 vs. 8.55 ± 2.87 points, respectively; p = 0.032). There were no differences in any of the T parameters or in the selective score among participants who never, occasionally, or regularly consumed alcohol. Therefore, we added the presence or absence of a smoking habit as a parameter to be adjusted for in logistic regression analysis.
We used the T concentrations recommended for the diagnosis of LOH by the EAU and AUA [11, 12]. TT <2.5 ng/dL and FT <7.5 pg/mL were used, because they are likely to become the new recommended thresholds in Japan [15]. We also used a cBT value of 1.84 ng/mL as the median level in the present study. We found that TT <3.5 ng/dL, TT <3.0 ng/dL, or TT <2.5 ng/dL, FT <8.5 pg/mL or FT <7.5 pg/mL, and cFT <65 pg/mL, significantly affected the probability of a selective score ≥10 points (Table 5), but not of ≥9 points (data not shown), after adjustment for age, Waist C, HOMA-IR, and smoking.
| Odds ratio | 95% CI | p | ||
|---|---|---|---|---|
| TT (<3.5 = 1, ≥3.5 = 2) | 0.480 | 0.232 | 0.996 | 0.049 |
| TT (<3.0 = 1, ≥3.0 = 2) | 0.315 | 0.106 | 0.937 | 0.038 |
| TT (<2.5 = 1, ≥2.5 = 2) | 0.098 | 0.010 | 0.908 | 0.041 |
| FT (<8.5 = 1, ≥8.5 = 2) | 0.352 | 0.188 | 0.659 | 0.001 |
| FT (<7.5 = 1, ≥7.5 = 2) | 0.390 | 0.183 | 0.831 | 0.015 |
| cFT (<65 = 1, ≥65 = 2) | 0.430 | 0.221 | 0.837 | 0.013 |
| cBT (<1.84 = 1, ≥1.84 = 2) | 0.788 | 0.421 | 1.473 | 0.455 |
TT, total testosterone; FT, free testosterone; cFT, calculated free testosterone; cBT, calculated bioavailable testosterone; HOMA-IR, homeostatic model assessment of insulin resistance. TT <3.5 ng/mL or TT <3.0 ng/mL is recommended for the diagnosis of LOH by the European Association of Urology or American Urological Association, respectively [11, 12]. In Japan, an FT <8.5 pg/mL is the recommended concentration at which T replacement should be considered in men with LOH [13], but both TT <2.5 ng/dL and FT <7.5 pg/mL are likely to become the new thresholds [15]. cFT <65 pg/mL is recommended by the EAU for the diagnosis of LOH [11]. The median concentration of cBT in the present study was 1.84 ng/mL.
The prevalence of FT <8.5 pg/mL was 30.2% (70/232). When using a selective score of ≥10, on the basis of the above Japanese criteria, to screen for LOH, the sensitivity was 55.7% (39/70) and the specificity was 72.2% (117/162). When a selective score of ≥10 was applied for diagnosis of LOH based on an FT <8.5 pg/mL [13], the prevalence of LOH among the participants was 16.8% (39/232).
The AMS scale and ADAM questionnaire were developed to identify androgen deficiency, in order to diagnose LOH. However, neither the AMS scale, nor the ADAM questionnaire, showed sufficient sensitivity (57.4% or 66.7%) or specificity (48.1% or 25.6%) for the identification of LOH in 339 men aged 47–65 years when using the diagnostic criteria for LOH of both TT <300 ng/dL and FT <5 ng/dL [8]. In addition, Tancredi et al. showed high sensitivity (81%) and low specificity (21.6%) for the AMS scale [9], and Chen et al. [16] showed that the sensitivity and specificity of the AMS scale were 54.0% and 41.2%, compared with 78.7% and 14.8% for the ADAM questionnaire. Because of these low specificities of the AMS scale and ADAM questionnaire, the usefulness of these questionnaires for the screening of men for LOH has been questioned. Indeed, the use of validated questionnaires including the AMS scale are not recommended for the diagnosis of hypogonadism according to the EAU or AUA guideline [11, 12].
Low libido alone (item No. 1 in the ADAM questionnaire) had better specificity (66.7% [17] or 75.5% [18]) for LOH than the entire questionnaire. Furthermore, the three sexual symptoms of low frequency of morning erections, low frequency of sexual thoughts, and erectile dysfunction, were significantly associated with biochemical T deficiency in men aged >40 y in the EMAS report [19]. Therefore, in the present study, we aimed to determine the most effective questionnaire items for the detection of T deficiency in middle-aged men, using the Japanese LOH guideline threshold of FT <8.5 pg/mL. The sexual symptoms corresponding to Nos. 15, 16, and 17 on the AMS scale were found to be sensitive means of detecting low values of various T parameters in our linear regression analysis. However, after adjustment for age, the sum of only the values of these three sexual scores (the selective sexual score) did not correlate with any of the T parameters. Interestingly, however, the newly-defined selective score, which includes the three sexual questions, plus No. 10 related to the awareness of muscle weakness, was found to be the most sensitive means of detecting low T concentration, even after adjustment for age.
Close relationships between T parameters and muscular strength in older men have been demonstrated in several clinical studies: the free T index (TT/SHBG ratio) was shown to be directly associated with arm and leg strength in aging men [20], and T replacement therapy in older men with low serum T concentration improved their muscular strength over 36 months [21]. These results suggest that the diagnostic utility of low T concentration could be enhanced by adding the muscle weakness score to the sexual items. This was found to hold true for the proposed selective score, which is unique in that no previous studies regarding screening for LOH have assessed the usefulness of questions regarding muscle weakness.
Another interesting finding of the present study is the suggestion that a selective score of ≥10 might be useful for the detection of FT <8.5 pg/mL, the concentration that represents the upper threshold for LOH in the Japanese criteria. The sensitivity (55.7%) and specificity (72.2%) of this selective score for the detection of FT <8.5 pg/mL is promising, compared with the low specificity (14% to 40%) of the AMS questionnaire [8, 9, 16]. The selective score also seems to be appropriate for the identification of individuals with T concentrations below the recommended values, cFT <65 pg/mL for the diagnosis of symptomatic LOH (as shown in Table 5).
The revision of clinical practice guidelines for LOH is currently underway in Japan, and a TT of <2.5 ng/mL and a FT of <7.5 pg/mL are likely to become the new thresholds [15]. Even after these new values have been applied in Japan, a selective score ≥10 was also found to be useful in the screening for LOH in this study (Table 5).
The selective score also seems to be most useful for the detection of T deficiency, according to the criteria of international bodies. Statistical analysis revealed that the selective score is affected by factors related to insulin resistance (Waist C and HOMA-IR) and smoking. This is unsurprising, because insulin resistance [4] and smoking [22] are well known to be associated with sexual dysfunction. However, even after adjustment for age, Waist C, HOMA-IR, and smoking, TT <3.5 ng/dL, TT <3.0 ng/dL or TT <2.5 ng/dL, FT <7.5 pg/mL or FT <8.5 pg/mL, and cFT <65 pg/mL were found to independently contribute to a selective score ≥10 points. Thus, a selective score ≥10 points seems to be a useful threshold for the detection of relative T deficiency, independent of age, smoking, and insulin resistance.
There were several limitations to the present study. First, there were relatively few participants (n = 234) and they were all Japanese. It remains to be determined whether our findings are specific to Japanese men or can be more widely applied. Second, the participants in the present study were individuals who visited a hospital for routine check-up. Therefore, the prevalence of T deficiency was not expected to be high, but in fact, almost 60% of the participants had an abnormal total AMS score. This might have affected the sensitivity and specificity calculated for the selective score in the present study. Therefore, in our proposed questionnaire, the selective score might be more useful for the detection of T deficiency in outpatients who are symptomatic or for whom there is a suspicion of LOH. A trial of such a group would be important for the evaluation of the new questionnaire.
In conclusion, in the screening for T deficiency and LOH, we propose the use of a simple questionnaire consisting of only four questions derived from the AMS: No. 10 (decrease in muscle strength), No. 15 (decrease in the ability to perform sexually or the frequency), No. 16 (decrease in the frequency of morning erections), and No. 17 (decrease in sexual desire/libido). A selective score ≥10 might be useful for the identification of individuals with FT <8.5 pg/mL, who might benefit from treatment with T, according to the Japanese guidelines. The validity of this simple questionnaire for use in the screening for LOH requires further investigation.
This research was supported by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (ID: 23390248). We thank Kusamoto K, Ochi M, Onimaru T, and Makita R in the Department of Preventive Medicine of Iizuka Hospital for their help with this study. We also wish to thank Masashi Ishizu (Department of Preventive Medicine, Tokushima University Graduate School of Biomedical Sciences) for help with the statistical analysis, and Edanz (https://jp.edanz.com/ac) for editing drafts of this manuscript.
None of the authors have any potential conflicts of interest associated with this research.
