Androgen deficiency in men has attracted much

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1 Journal of Andrology, Vol. 33, No. 5, September/October 2012 Copyright E American Society of Andrology The Comparison of the Aging Male Symptoms (AMS) Scale and Androgen Deficiency in the Aging Male (ADAM) Questionnaire to Detect Androgen Deficiency in Middle-Aged Men KUANG-SHUN CHUEH,* SHU-PIN HUANG,*{ YUNG-CHIN LEE,*{{ CHII-JYE WANG,*{ HSIN-CHIH YEH,*{ WEI-MING LI,*{5 WEN-JENG WU,*{" YUEH-FONG TSAI,* CHIA-CHUN TSAI,* HSU-CHENG JUAN,* CHUN-HSIUNG HUANG,*{ AND CHIA-CHU LIU*{{5 From the *Department of Urology, Kaohsiung Medical University Hospital, the ÀDepartment of Urology, Faculty of Medicine, College of Medicine, and the `Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; the Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; the 5Pingtung Hospital, Department of Health, Executive Yuan, Pingtung, Taiwan; and the "Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan. ABSTRACT: The prevalence of androgen deficiency in men increases with aging. Two common instruments, the Aging Male Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire, are often used to screen for androgen deficiency in clinical practice. The aim of this study is to compare the capability of the AMS scale and the ADAM questionnaire to detect androgen deficiency in middle-aged Taiwanese men. In April 2008, a free health screening was conducted by Kaohsiung Medical University Hospital. All participants completed a health questionnaire and had blood samples drawn between 8:00 AM and noon. Serum total testosterone (TT), albumin, and sex hormone binding globulin levels were measured. The level of free testosterone (FT) was calculated. Clinical symptoms associated with androgen deficiency were screened by using the AMS scale and ADAM questionnaire. Androgen deficiency was defined as TT, 300 ng/dl or both TT, 300 ng/dl and FT, 5ng/dL. In total, 339 men were included in the final analysis, with the mean age of years (range, years). Androgen deficiency was found in 75 men (22.1%) based on the criteria of TT, 300 ng/dl, and in 54 men (15.9%) based on the criteria of TT, 300 ng/ dl and FT, 5ng/dL. When detecting participants with both TT, 300 ng/dl and FT, 5ng/dL, the sensitivity and specificity of the AMS scale were 57.4% and 48.1%, compared with 66.7% and 25.6% for the ADAM questionnaire. In a sample of middle-aged Taiwanese men, neither the AMS scale nor the ADAM questionnaire had sufficient sensitivity and specificity to detect androgen deficiency. In addition to using those 2 screening instruments, a thorough physical and biochemical workup should still be conducted in patients at risk or suspected of androgen deficiency. Key words: Testosterone, AMS scale, ADAM questionnaire. J Androl 2012;33: Androgen deficiency in men has attracted much medical interest in recent years (Nieschlag et al, 2005; Bhasin et al, 2006). Unlike menopause, in which all women undergo a nearly complete cessation of gonadal estrogen production, gonadal androgen production in men decreases progressively after the age of 40 years. Previous studies showed that serum testosterone levels decline between 0.4% and 2.6% per year in men after age 40 (Harman et al, 2001; Feldman et al, 2002). Supported by grants from the Taiwan National Science Council (NSC B MY3; NSC B MY3) and Kaohsiung Medical University Hospital (KMUH99-9R13; KMUH99-9R14; KMUH100-0R43; KMUH100-0R45). Correspondence to: Dr Chia-Chu Liu, Department of Urology, Kaohsiung Medical University Hospital, 100 Tz-You 1st Rd, Kaohsiung, Taiwan ( m @hotmail.com). Received for publication October 16, 2011; accepted for publication January 11, DOI: /jandrol The clinical signs and symptoms of androgen deficiency include diminished sexual desire and erectile function, depression, lethargy, osteoporosis, regression of secondary sexual characteristics, and loss of muscle mass and/or strength. Other sequelae include diminished interest in activities, sleep disturbance, deteriorating work performance, and inability to concentrate (Nieschlag et al, 2005; Bhasin et al, 2006). In addition to decreased quality of life (Maggi et al, 2007), androgen deficiency has been associated with increased risks of comorbidities, including erectile dysfunction (Hwang and Lin 2008; Traish et al, 2009a), metabolic syndrome (Laaksonen et al, 2004; Traish et al, 2009a), diabetes mellitus (Laaksonen et al, 2004; Ding et al, 2006; Traish et al, 2009c), osteoporosis and bone fracture (Isidori et al, 2005), and cardiovascular disease (Maggio and Basaria 2009; Traish et al, 2009b). Furthermore, some studies have found links between androgen deficiency and higher risk of premature death in elder men (Khaw et al, 2007; Laughlin et al, 2008). For the mentioned 817

2 818 Journal of Andrology N September ÙOctober 2012 reasons, androgen deficiency is proposed as an important warning sign for poor health in men (Liu et al, 2009; Maggio and Basaria 2009), and detection of subjects at risk or suspected of androgen deficiency has become an area of interest in recent years. The Aging Male Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire are 2 questionnaires widely used today for screening men suspected of androgen deficiency. The ADAM questionnaire was developed by Morley et al in It is used as a screening tool to detect men at risk of androgen deficiency. This questionnaire is highly oriented towards the Western world, and high sensitivity (,81% 97%) but poor specificity (,16% 30%) to detect androgen deficiency have been reported (Tancredi et al, 2004; Morley et al, 2006; Martinez-Jabaloyas et al, 2007). Another questionnaire, the AMS scale, was first published in Germany in This questionnaire has been developed mainly for 2 purposes: to 1) evaluate the severity of aging male symptoms in older men and 2) follow the improvement after androgen therapy (Heinemann et al, 1999). It also plays an important role in the screening of androgen deficiency. A sensitivity of 83% with a specificity of 59% to detect androgen deficiency has been reported (Morley et al, 2006). Although both questionnaires have been used globally to screen and evaluate symptoms of androgen deficiency, the efficiency of these 2 questionnaires to detect androgen deficiency remains controversial. Aim Androgen deficiency has been proposed as an important warning sign of poor health in men (Liu et al, 2009; Maggio and Basaria 2009). Thus, detection of subjects at risk or suspected of androgen deficiency is very important. Although some studies have reported the efficiency of the AMS scale and ADAM questionnaire to detect androgen deficiency in Caucasian populations (Tancredi et al, 2004; Morley et al, 2006; Martinez- Jabaloyas et al, 2007), data from other ethnicities are still lacking. The aim of this study is to evaluate the sensitivity and specificity of the AMS scale and the ADAM questionnaire to detect androgen deficiency in middle-aged Taiwanese men. Materials and Methods A free health screening for men older than 40 years was conducted by the Kaohsiung Medical University Hospital in Kaohsiung, Taiwan, in April The screening was open to the general male population living in the city of Kaohsiung. The study protocol was approved by the Institutional Review Board of the Kaohsiung Medical University Hospital, and all subjects provided informed consent before their participation. Men with malignancy or liver cirrhosis, or currently (within the last month) on medication that can influence serum testosterone levels, including hormones, antiandrogen or antifungal agents, and steroidal agents, were excluded. At this screening, each participant received a detailed physical examination and answered questionnaires to collect their demographic information and medical histories. Both the ADAM questionnaire and the AMS scale were used to assess the clinical symptoms of androgen deficiency in each participant. The ADAM questionnaire is a 10-item screening tool for identifying androgen deficiency in aging men (Morley et al, 2000). If a participant responds affirmatively to decreased libido or strength of erection, or gives a positive response to any 3 of the nonspecific questions including fatigability, decreased muscle strength, mood change, and loss of height, he is considered as having symptoms suggestive of androgen deficiency. The AMS scale includes 17 questions to assess symptoms that are supposed to be associated with androgen decline in aging males (Heinemann et al, 1999; Chen et al, 2007). Each question is to be answered on a scale from 1 to 5. The 17 questions comprise 3 subscales psychological, somatic, and sexual symptoms and can be summed up to a total score. The psychological subscale consists of the items of depressive mood, being burned out, increased irritability, anxiety, and nervousness; the somatic subscale consists of increased joint complaints, increased sweating, need for more sleep, impaired well-being, increased sleep disturbances, muscular weakness, physical exhaustion, and decrease of beard growth; the sexual subscale consists of impaired sexual potency, fewer morning erections, disturbed libido, and feelings that the subject has passed his peak. A total score $27 has been defined as suggestive of androgen deficiency (Heinemann et al, 1999; Chen et al, 2007). Hormone Analysis All participants had nonfasting blood samples drawn between 8:00 AM and noon on the day of screening. This time frame was chosen to minimize natural diurnal variation in hormone levels. Serum albumin, total testosterone (TT), and sex hormone binding globulin (SHBG) levels in each sample were measured. Serum albumin was measured using a Beckman CX-7 chemistry analyzer (Global Medical Instrumentation, Ramsey, Minnesota), which had an interassay coefficient of variation (CV) of 3.6% and an intra-assay CV of 2.2% (Liu et al, 2007, 2009). TT levels (detectable range, ng/dl; interassay CV of 8.4%; intra-assay CV of 5.2%) and SHBG levels (detectable range, nmol/l; interassay CV of 4.8%; intra-assay CV of 3.5%) were determined using a DPC Immulite analyzer (Diamond Diagnostics, Holliston, Massachusetts; Liu et al, 2007, 2009). Free testosterone (FT) level was calculated from TT, SHBG, and albumin according to the Vermeulen formula (Vermeulen et al, 1999). The definitions of androgen deficiency were based on the Endocrine Society s clinical practice guideline for the diagnostic evaluation of adult men suspected of having androgen deficiency (Bhasin et al, 2006). TT level,300 ng/dl or TT level,300 ng/dl and FT level,5 ng/dl were defined as androgen deficiency (Bhasin et al, 2006; Liu et al, 2009).

3 Chueh et al N AMS Scale and ADAM Questionnaire 819 Table 1. Baseline characteristics of subjects (n 5 339) Parameter No. (%) Mean 6 SD Range Age, y Educational status At least some college 207 (61.1) Secondary/high school 123 (36.2) Primary school or less 9 (2.7) BMI, kg/m Normal weight (BMI, 24) 124 (36.6) Overweight (24, BMI # 27) 150 (44.2) Obesity (BMI. 27) 65 (19.2) Comorbidities Diabetes mellitus 21 (6.2) Hypertension 74 (21.8) Hyperlipidemia 50 (14.7) Cardiovascular disease 12 (3.5) Current smoking 40 (11.8) Current alcohol drinking 52 (15.3) Endocrinologic TT, ng/dl FT, ng/dl SHBG, nmol/l Albumin, g/dl Androgen deficiency TT,300 ng/dl 75 (22.1) TT,300 ng/dl and FT,5 ng/dl 54 (15.9) Abbreviations: BMI, body mass index; FT, free testosterone; SHBG, sex hormone binding globulin; TT, total testosterone. Statistical analyses Data were expressed as mean 6 SD unless otherwise indicated. The correlations between different parameters were estimated by Spearman correlation coefficients. The Statistical Package for Social Sciences, version 12.0 (SPSS, Chicago, Illinois), was used for statistical analyses. A P value of less than.05 was considered significant. Results In total, 371 men participated in this free health screening. Among these men, 32 men were excluded because of malignancy (10 men) and use of medicines that may influence testosterone level (22 men). A total of 339 men were included in the final analysis. Among these 339 men, the mean age was years (range, years). Androgen deficiency was found in 75 men (22.1%) based on the criteria of TT, 300 ng/dl, and in 54 men (15.9%) based on the criteria of TT, 300 ng/dl and FT, 5ng/ dl. The baseline characteristics and endocrine parameters of the participants are summarized in Table 1. The comparison of the AMS scale and the ADAM questionnaire for detecting TT, 300 ng/dl and both TT, 300 ng/dl and FT, 5ng/dLisshowninTable2.If androgen deficiency is defined as TT, 300 ng/dl, the AMS scale showed sensitivity of 57.3%, specificity of 48.5%, positive predictive value of 24.0%, and negative predictive value of 80.0%. The ADAM questionnaire showed sensitivity of 72.0%, specificity of 26.5%, positive predictive value of 21.8%, and negative predictive value of 76.9% (Table 2). If androgen deficiency is defined as both TT, 300 ng/dl and FT, 5 ng/dl, the AMS scale showed sensitivity of 57.4%, specificity of 48.1%, positive predictive value of 17.3%, and negative predictive value of 85.6% to detect androgen deficiency. The ADAM questionnaire showed sensitivity of 66.7%, specificity of 25.6%, positive predictive value of 14.5%, and negative predictive value of 80.2% (Table 2). We also use the reference value of androgen deficiency in our laboratory, which is defined as TT, 280 ng/dl, for sensitivity testing. The AMS scale showed sensitivity of 56.9% and specificity of 47.9%, and the ADAM questionnaire showed sensitivity of 66.7% and specificity of 25.7%, which were similar to previous results using definitions of TT, 300 ng/dl and both TT, 300 ng/dl and FT, 5ng/ dl. In addition, the results of the AMS scale were positively correlated with results of the ADAM questionnaire in our study population (r , P,.001).

4 820 Journal of Andrology N September ÙOctober 2012 Table 2. The comparison of capability of the AMS scale and the ADAM questionnaire to detect TT, 300 ng/dl and both TT, 300 ng/dl and FT, 5ng/dL Yes No Total Sensitivity, % Specificity, % PPV, % NPV, % TT, 300 ng/dl AMS scale Positive Negative ADAM questionnaire Positive Negative TT, 300 ng/dl and FT, 5ng/dL AMS scale Positive Negative ADAM questionnaire Positive Negative Abbreviations: ADAM, Androgen Deficiency in the Aging Male; AMS, Aging Male Symptoms; FT, free testosterone; NPV, negative predictive value; PPV, positive predictive value; TT, total testosterone. Discussion Recently, androgen deficiency has been found to increase risks for a lot of chronic diseases (Maggio and Basaria 2009; Traish et al, 2009b,c) and even premature death (Khaw et al, 2007; Laughlin et al, 2008) in aging men. Thus, early detection of androgen deficiency has become an important topic. In healthy, young, eugonadal men, serum TT levels generally range from 300 to 1050 ng/dl. Previous longitudinal and cross-sectional studies have shown that a man s serum testosterone levels decrease by 0.4% to 2.6% per year after age 40 (Harman et al, 2001; Feldman et al, 2002). Some studies have proposed that a TT level below 300 ng/dl, measured in the morning, can be considered a threshold for androgen deficiency (Mulligan et al, 2006; Orwoll et al, 2006). Others suggested that androgen deficiency in patients with lower TT levels (below 300 ng/dl) should be confirmed by testing the levels of FT (below 5 ng/dl), on the basis that the concentration of FT might correlate better with the biological activities of androgen (Bhasin et al, 2006; Araujo et al, 2007; Liu et al, 2009). However, there is still lack of consensus with regard to the threshold of testosterone levels for the diagnosis of androgen deficiency. Several questionnaires like the AMS scale and the ADAM questionnaire have been proposed to screen men at risk or suspected of androgen deficiency. Our study found that the ADAM questionnaire has relatively good sensitivity but poor specificity to detect androgen deficiency in middle-aged Taiwanese men based on criteria of TT, 300 ng/dl and both TT, 300 ng/dl and FT, 5 ng/dl (Table 2). However, the AMS scale seemed to have relatively low sensitivity and specificity to detect androgen deficiency in our study population. Previously, some studies have evaluated the efficacy of using both the AMS scale and the ADAM questionnaire to detect androgen deficiency, but the results have not been consistent. Morley and colleagues used the AMS scale and ADAM questionnaire to screen for androgen deficiency, which was defined as bioavailable testosterone, 70 ng/dl, in 148 men aged years (Morley et al, 2006). They found that the sensitivities of the AMS scale and the ADAM questionnaire were 83% and 97%, and the specificities were 59% and 30%. They concluded that both the ADAM questionnaire and the AMS scale can serve as good screening tests for androgen deficiency (Morley et al, 2006). However, Tancredi and colleagues (2004) used the ADAM questionnaire to screen for androgen deficiency, which was defined as FT, 7 ng/dl, in 5028 men aged years. The sensitivity and specificity were 81% and 21.6%, respectively. They suggested that the ADAM questionnaire could not be used for the diagnosis of androgen deficiency because of its low specificity rate. Similar results were also found by Chu and colleagues (2008) in the study of a Chinese population. They used the ADAM questionnaire to detect androgen deficiency, which was defined as bioavailable testosterone, 71 ng/dl, in 796 men aged years. The sensitivity and specificity were 86% and 40%, respectively. They concluded that the ADAM questionnaire is a sensitive but not specific screening

5 Chueh et al N AMS Scale and ADAM Questionnaire 821 Table 3. The results of using the Androgen Deficiency in the Aging Male questionnaire to detect androgen deficiency Study No. of Patients Age, y Definition for Androgen Deficiency Sensitivity, % Specificity, % PPV, % NPV, % Our study TT, 300 ng/dl TT, 300 ng/dl and FT, 5ng/dL Eastern Chu et al, 2008 (China) BT, 71 ng/dl Western Tancredi et al, 2004 (Belgium) FT, 7ng/dL Martinez-Jabaloyas et al, 2007 (Spain) FT, 6.6 ng/dl Morley et al, 2006 (United States) BT, 70 ng/dl Abbreviations: BT, bioavailable testosterone; FT, free testosterone; NPV, negative predictive value; PPV, positive predictive value; TT, total testosterone. test for androgen deficiency in Chinese men. Table 3 summarizes the results of using the ADAM questionnaire to detect androgen deficiency in our study and other studies (Tancredi et al, 2004; Morley et al, 2006; Martinez-Jabaloyas et al, 2007; Chu et al, 2008). The sensitivity ranged from 66.7% to 97% and the specificity ranged from 21.6% to 40%. Although the definitions of androgen deficiency in those studies were different, their results implied that the ADAM questionnaire might serve as a relatively sensitive but not specific screening test for androgen deficiency. In addition, a relatively low correlation was found between the results of the AMS scale and the ADAM questionnaire in our study (r , P,.001). A German study using the AMS scale to predict the results of the ADAM questionnaire in 150 men aged years showed similar findings. These authors (Heinemann et al, 2004) found that the positive predictive value and negative predictive value were 92% and 50% respectively. Several questionnaires, including the AMS scale and the ADAM questionnaire, have been proposed to screen for androgen deficiency; however, the results of these questionnaires could easily be affected by other chronic diseases, malignancy, depressive disorder, and stress (Morales et al, 2007). A Japanese study reported that a strong correlation was found between the AMS scale and a major depressive disorder (Yoshida et al, 2006). Unfortunately, depression is very common in elderly people and may therefore cause some bias when using these questionnaires to detect androgen deficiency. In our study, the AMS scale had both low sensitivity and low specificity to detect androgen deficiency in middle-aged Taiwanese men. Although the ADAM questionnaire seemed to have a satisfactory sensitivity to detect androgen deficiency in our study population, its poor specificity should be noted and it should be pointed out that the ADAM questionnaire cannot be used to replace biochemical methods to diagnose androgen deficiency. Moreover, only a proportion of men presenting with low testosterone levels do have sexual, physical, or psychological symptoms of hypogonadism (Wu et al, 2010), which also mean that tests such as AMS and ADAM cannot be good instruments in showing low testosterone levels. Further work is needed to provide new, more robust questionnaires to screen for androgen deficiency in clinical practice. In addition to age, several independent risk factors for androgen deficiency have been reported, including obesity, diabetes, and increased numbers of comorbidities and medications (Travison et al, 2007; Wu et al, 2008; Liu et al, 2009). In clinical practice, a thorough physical and biochemical workup should still be conducted to evaluate the risk of androgen deficiency. There are some more specific symptoms and signs for androgen deficiency like reduced sexual desire (libido) and activity, decreased spontaneous erections, gynecomastia, loss of body (axillary and pubic) hair, reduced shaving, shrinking testes, height loss, low bone mineral density, hot flushes, and sweats, which should be included in clinical evaluation (Bhasin et al, 2006, 2010). In subjects with significant risk factors, further biochemical evaluation of their serum androgen levels should be considered. Conclusion In a sample of middle-aged Taiwanese men, both the AMS scale and the ADAM questionnaire did not have sufficient sensitivity and specificity to detect androgen deficiency. In addition to the use of these 2 screening instruments, a thorough physical and biochemical workup should still be conducted in men at risk or

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