Are the Aging Male’s Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire suitable for the screening of late-onset hypogonadism in aging Chinese men?

Abstract

The Aging Male’s Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire have been widely used for screening men suspected of late-onset hypogonadism (LOH). We evaluated the consistency of the two questionnaires with sex hormone levels. A total of 985 men completed the two questionnaires, as well as an analysis of the serum levels of total testosterone (TT), bioavailable testosterone (BT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL) and sex hormone-binding globulin (SHBG). No correlation was observed between any hormone level and the psychological or somatic section of the AMS score, whereas the sexual section was correlated with the levels of FT, LH, FSH, SHBG and BT. Significant correlations were observed between the result of the two questionnaires and these hormone levels. When LOH was defined as TT < 300 ng/dl and FT < 5 ng/dl, 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. Several sex hormone levels correlated with the two questionnaires, but neither of these questionnaires had sufficient sensitivity and specificity. It is necessary to provide a new questionnaire applicable to the Chinese population to screening LOH.

• ADAM
• AMS
• late-onset hypogonadism
• sex hormone

Introduction

Androgen deficiency in the aging male has become an interesting and debatable topic throughout the world [1,2]. Late-onset hypogonadism (LOH) is defined as a clinical and biochemical syndrome that is associated with advancing age and is characterized by symptoms and a deficiency in serum testosterone levels [2–5]. The symptoms associated with the decline in testosterone include a loss of muscle mass and strength, cognitive decline, diminished sexual desire and erectile quality, decrease in bone mass and increase in fat mass. However, it is difficult to diagnose LOH in clinical practice for the following reasons. Firstly, there are still no accepted lower limits for the normal serum testosterone level. Secondly, the symptoms associated with LOH are not specific for diagnosis because these manifestations can also be influenced by other factors, such as urban stress and a fast-paced life.

The Aging Male’s Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire have been widely used for screening men suspected of LOH. The AMS scale, first published in Germany in 1999, has been developed to evaluate the severity of aging male symptoms and measure changes after androgen replacement therapy [6]. The ADAM questionnaire, which was developed by Morley et al. in 2000, has been considered to be one of the most efficient clinical tools for assessing testosterone deficiency [7]. Although these two questionnaires have been used globally to screen and evaluate the symptoms of LOH, their efficiency remains controversial because of their low specificity [8–10]. Another questionnaire, the Massachusetts Male Aging Study (MMAS), has been developed as a potential screening tool for LOH in older males [11]. The MMAS is mainly a risk questionnaire, rather than a symptom questionnaire. Because of its low sensitivity, the MMAS is insufficient to justify its use as a screening test and has never been widely used. There are two screening instruments attempting to develop the efficiency, including ANDROTEST [12] and NERI hypogonadism screener [13], which are also not been widely used.

Several studies have focused on the relationship between sex hormone levels and the AMS scale or ADAM questionnaire [10,14]. To the best of our knowledge, there has been no similar study performed in a Chinese population. The aim of this study is to evaluate whether the AMS scale and ADAM questionnaire have consistency with sex hormone levels for screening for LOH and to assess the efficiency of the two questionnaires in the Chinese population. In a word, we want to know whether the AMS scale and ADAM questionnaire are suitable for identifying LOH in the Chinese population.

Methods

Participants

This study was performed on local male residents of nine communities of Pudong District, Shanghai, China. This study was approved by the Institution Review Board, Changhai Hospital, Second Military Medical University, Shanghai, China. All of the subjects provided written informed consent before their participation. Men with endocrine diseases, prostate diseases requiring anti-androgen therapy, and psychological diseases were excluded.

The AMS scale and ADAM questionnaire

All of the participants completed the AMS scale and ADAM questionnaire. The AMS scale is comprised of 17 questions to evaluate symptoms that are supposed to be related to LOH in aging males. These questions comprise three subscales that include psychological, somatic and sexual symptoms. Each question is to be answered with a score from 1 to 5. Next, a total score is obtained to assess the symptoms. A total score of 27 or more was considered to be positive. The ADAM questionnaire is a 10-item screening tool for identifying LOH in aging males. Answering yes to question 1 or 7 or any three or more of the other questions was defined as a positive score.

Laboratory assays

All of the participants provided non-fasting blood samples drawn between 8:00 and 11:00 AM. Serum aliquots of all of the blood samples were prepared and submitted to a biochemistry laboratory operated by our hospital for several sex hormone assays, including total testosterone (TT), bioavailable testosterone (BT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL) and sex hormone-binding globulin (SHBG). Each parameter was measured by a chemical or luminescent method (the instruments and reagents were produced by the Beckmann Co., Bremen, German). The free testosterone (FT) was calculated based on the TT, SHBG and albumin according to the Vermeulen formula [13]. A TT level <300 ng/dl or TT level <300 ng/dl and FT level <5 ng/dl were defined as LOH according to the Endocrine Society’s clinical practice guideline for diagnostic evaluation [1].

Statistical analysis

The statistical analysis was performed using the Statistical Package for Social Sciences 17.0 software (SPSS Inc., Chicago, IL). The data were expressed as the means ± standard deviation (SD). The correlations between different parameters were analyzed by Spearman correlation coefficients or regression analysis as appropriate. All of the continuous variables were analyzed by either a two-tailed Student’s t test or a one-way analysis of variance as appropriate. A p value of less than 0.05 was considered to be significant.

Results

In total, 1000 men participated in this screening. Among all of the subjects, 15 men were excluded due to endocrine and prostate diseases that might influence the hormone levels. Thus, a total of 985 men (mean age 59.4 ± 7.4 years) were included in the final analysis. The summaries of the AMS and ADAM scores and the sex hormone levels are shown in Table 1. According to the AMS scale, 568 (568/985, 57.66%) men were defined as positive, whereas 824 (824/985, 83.65%) were defined as positive by the ADAM questionnaire.

Table 1. Summaries of AMS, ADAM scores and sex hormone levels.

	N (%)	Mean	SD
	985
AMS scores
Positive	568 (57.66%)
Negative	417 (42.34%)
ADAM scores
Positive	824 (83.65%)
Negative	161 (16.35%)
TT (ng/dl)		443.95	133.53
FT (ng/dl)		8.21	2.64
LH (IU/l)		5.69	3.05
FSH (U/l)		11.34	7.36
E2 (pg/ml)		34.67	14.71
PRL (μg/l)		10.83	7.69
SHBG (nmol/l)		44.87	23.77
BT (ng/dl)		174.8	61.48

The correlation between age, AMS scores and sex hormone levels is shown in Table 2. The levels of FT and BT significantly decreased with age. Moreover, there was a significant increasing trend in the LH, FSH and SHBG levels with age. There was no correlation between the levels of TT, E2 or PRL and age. There was no correlation between any sex hormone level and the psychological or somatic sections of the AMS score. However, several correlations were observed between the sexual section of the AMS score and FT, LH, FSH, SHBG and BT. We also observed a similar correlation between the total AMS scores and these sex hormone levels.

Table 2. Correlation of age, AMS scores and sex hormone levels.

Correlation		AMS score
coefficient	Age	Psychological	Somatic	Sexual	Total
Age (years)	–	0.02	0.14***	0.39***	0.26***
TT (ng/dl)	−0.04	−0.05	−0.02	−0.02	−0.05
FT (ng/dl)	−0.30***	−0.06	−0.04	−0.12**	−0.12***
LH (IU/l)	0.32***	−0.01	0.06	0.15***	0.11**
FSH (U/l)	0.37***	0.02	0.08	0.15**	0.12***
E2 (pg/ml)	0.06	−0.01	−0.02	0.03	−0.01
PRL (μg/L)	−0.05	0.01	0.01	0.06	0.03
SHBG (nmol/l)	0.31***	−0.01	0.02	0.12**	0.08*
BT (ng/dl)	−0.34***	−0.04	−0.04	−0.12**	−0.11**

*p < 0.05; **p < 0.01; ***p < 0.001.

The severity of the symptoms was divided into four categories (no/little, mild, moderate and severe) based on four AMS total score intervals, including ≤26, (27--36), (37--49), and ≥50 [15–17]. We found that there was no association between the sex hormone levels and the severity of the symptoms according to the AMS scores, except that LH increased with the severity of the symptoms (p = 0.001). We also found that the severity of the symptoms increased with aging (p < 0.001) (Table 3).

Table 3. Association of age, severity of the symptoms according to the AMS score and sex hormonal levels.

	AMS score
Variables	No/little	Mild	Moderate	Severe
Age (years) *	57.64 ± 6.95	59.95 ± 7.21	62.44 ± 7.90	61.92 ± 7.69
TT (ng/dl)	447.60 ± 122.97	442.19 ± 138.40	435.90 ± 141.01	454.39 ± 160.79
FT (ng/dl)	8.49 ± 2.48	7.98 ± 2.68	8.02 ± 2.93	8.34 ± 2.49
LH (IU/l)*	5.34 ± 2.60	5.79 ± 2.98	6.06 ± 4.10	6.91 ± 3.04
FSH (U/l)	10.48 ± 6.63	12.17 ± 8.52	11.63 ± 6.08	10.55 ± 5.07
E2 (pg/ml)	34.73 ± 14.50	34.10 ± 13.90	36.15 ± 17.08	34.21 ± 15.82
PRL (μg/l)	10.99 ± 9.27	10.21 ± 5.22	11.76 ± 8.38	12.07 ± 7.02
SHBG (nmol/l)	42.71 ± 21.17	46.34 ± 23.65	47.03 ± 30.36	44.79 ± 21.58
BT (ng/dl)	182.33 ± 57.51	168.09 ± 61.76	171.48 ± 70.25	178.08 ± 56.75

*p < 0.001

As shown in Table 4, in the AMS questionnaire, in terms of age and the levels of FT, LH, FSH, SHBG and BT, there was a significant difference between the positive and negative groups. A significant correlation was observed between a positive or negative result of AMS and these sex hormone levels. A similar correlation was also found in the ADAM questionnaire. However, regardless of the AMS scale or ADAM questionnaire, no correlation was found between a positive or negative result and the hormone levels of TT, E2 and PRL.

Table 4. Asociation of age, AMS, ADAM scores, and sex hormone levels.

	AMS		ADAM
Associations	Positive	Negative	Positive	Negative
Age (years)	60.72 ± 7.50	57.64 ± 6.95***	60.19 ± 7.26	55.33 ± 6.97***
TT (ng/dl)	441.44 ± 140.40	447.60 ± 122.97	442.90 ± 135.04	450.07 ± 124.78
FT (ng/dl)	8.02 ± 2.73	8.49 ± 2.48***	8.09 ± 2.62	8.90 ± 2.63**
LH (IU/l)	5.94 ± 3.30	5.34 ± 2.60**	5.81 ± 3.15	5.03 ± 2.25*
FSH (U/l)	11.92 ± 7.78	10.48 ± 6.63***	11.60 ± 7.64	9.83 ± 5.24*
E2 (pg/ml)	34.62 ± 14.87	34.73 ± 14.50	34.52 ± 14.38	35.48 ± 16.41
PRL (μg/l)	10.71 ± 6.31	10.99 ± 9.27	10.75 ± 7.92	11.29 ± 6.33
SHBG (nmol/l)	46.42 ± 25.39	42.71 ± 21.17*	45.61 ± 24.31	40.90 ± 20.28**
BT (ng/dl)	169.62 ± 63.61	182.33 ± 57.51***	171.94 ± 61.08	191.46 ± 61.39**

*p < 0.05; **p < 0.01; ***p < 0.001.

We compared the results of the AMS scale and the ADAM questionnaire with two diagnostic standards (Table 5). When LOH was defined as TT < 300 ng/dl and FT < 5 ng/dl, the AMS scale showed a sensitivity of 54.0%, specificity of 41.2%, positive predictive value of 22.4% and negative predictive value of 74.1%. The ADAM questionnaire showed a sensitivity of 78.7%, specificity of 14.8%, positive predictive value of 22.5% and negative predictive value of 68.9%. When LOH was defined as TT < 300 ng/dl, the AMS scale showed a sensitivity of 56.0%, specificity of 41.5%, positive predictive value of 31.3% and negative predictive value of 66.4%. The ADAM questionnaire showed a sensitivity of 81.8%, specificity of 15.4%, positive predictive value of 31.6% and negative predictive value of 64.0%.

Table 5. The sensitivity and specificity of the AMS scale and ADAM questionnaire.

	AMS						ADAM
	Positive	Negative	Sensitivity	Specificity	PPV	NPV	Positive	Negative	Sensitivity	Specificity	PPV	NPV
TT < 300 ng/dl and  FT < 5 ng/dl	127	108	0.540	0.412	0.224	0.741	185	50	0.787	0.148	0.225	0.689
Others	441	309					639	111
Total	568	417					824	161
TT < 300 ng/dl	178	140	0.560	0.415	0.313	0.664	260	58	0.818	0.154	0.316	0.640
TT ≥ 300 ng/dl	390	277					564	103
Total	568	417					824	161

Discussion

In this study, we explored the relationship between the AMS scale, ADAM questionnaire and levels of sex hormones, such as TT, FT, LH, FSH, E2, PRL, SHBG and BT. Further, we evaluated the sensitivity and specificity of the two questionnaires for identifying LOH. We found that although the levels of certain hormones, such as FT, LH, FSH, SHBG and BT, have certain correlations with the AMS scale and ADAM questionnaire, because of the low sensitivity and specificity of the AMS scale and the relatively high sensitivity but low specificity of the ADAM questionnaire, these two questionnaires may be unsuitable for identifying LOH in aging Chinese men. We suggest that a new questionnaire that is appropriate for the Chinese population should be established in future studies.

In our study, the concentrations of FT and BT had significant negative correlations with age, whereas LH, FSH and SHBG had significant positive correlations with age, which was consistent with the results obtained by previous studies [10,14]. However, TT declined with aging but with no significance, which was different from other studies [10,18]. In a study performed by Beutel et al. [10], TT and FT significantly declined with aging. Similar results were also obtained by Feldman et al. [18]. However, Blumel et al. [19] found that TT levels fell with aging but without statistical significance, which was consistent with our results. Due to the inconsistency of the relationship between age and TT level, we suggest that the measurement of FT instead of TT should be considered for the diagnosis of LOH.

The efficiency of the AMS scale and ADAM questionnaire is mainly based on whether the results can reflect the levels of serum sex hormones. Therefore, it is necessary to assess the consistency between the two questionnaires and sex hormone levels. Several studies have focused on the association between sex hormone levels and the results of the two questionnaires. Emmelot-Vonk et al. [15] assessed the association between the concentration of serum testosterone and the symptoms of testosterone deficiency according to the AMS and ADAM questionnaires. These researchers found that there was no significant association between the total testosterone concentration and the scores on the two questionnaires. However, these researchers found that age was significantly associated with the scores on the two questionnaires. Another study performed by Miwa et al. [14] investigated the relationship between LOH-related symptoms evaluated by the AMS scale and several serum hormone levels. These authors found no correlation between age and AMS scores, and none of the three AMS domain scale scores or the total score was significantly correlated with any serum hormone level, including TT, FT, E2, LH, FSH, dehydroepiandrosterone sulfate (DHEA-S) or growth hormone (GH). In contrast, Basar et al. [20] found that serum TT and FT correlated significantly with the andrological symptoms of AMS, and the serum E2 levels correlated with the psychological symptoms of AMS. Different from previous studies, in our study, when the AMS score was divided into three subgroups, there was no correlation between any sex hormone level and the psychological or somatic subgroup. However, we found correlations among the sexual score and FT, LH, FSH, SHBG and BT, leading to the result that the total AMS score was correlated with these hormone levels, which indicated that the AMS questionnaire mainly reflected the sexual factor. When the severity of the symptoms according to the AMS score was divided into no or little, mild, moderate and severe subgroups, only the level of LH significantly increased with the change in the severity of the symptoms, and we thought that this value had limited clinical significance. Notably, when the subjects were divided into positive and negative groups according to the standard evaluated by the AMS questionnaire, the two groups were correlated with the levels of FT, LH, FSH, SHBG and BT, which was similar to the results obtained when the sexual score was compared with the hormone levels. Furthermore, using the ADAM questionnaire as the screening tool, we also found that the positivity and negativity of the ADAM questionnaire were associated with the levels of FT, LH, FSH, SHBG and BT. Therefore, we drew the conclusion that AMS scale and ADAM questionnaire could preliminarily estimate the serum levels of FT, LH, FSH, SHBG and BT.

Previous studies have evaluated the efficacy of using the AMS scale and ADAM questionnaire to detect LOH, but the results were not consistent [9,19,21,22]. Morley et al. [21] compared three questionnaires, specifically, ADAM, AMS and MMAS, for the diagnosis of hypogonadism using bioavailable testosterone as the biochemical gold standard. These authors suggested that the ADAM and AMS questionnaires, with sensitivities of 97% and 83%, respectively, and specificities of 30% and 39%, respectively, were useful in screening for hypogonadism across the adult lifespan. Chu et al. investigated the validity of the ADAM questionnaire in screening for LOH in Chinese men and found that this instrument had a high sensitivity of 88% but a low specificity of 32% [22]. These researchers concluded that the ADAM questionnaire was suitable for use as a screening test for LOH in Chinese men from 40 to 79-years-old. However, Tancredi et al. [9] evaluated the efficacy of the ADAM questionnaire for the identification of hypogonadism in elderly males. These authors found that the sensitivity and specificity of the ADAM score were 81% and 21.6%, respectively. Therefore, these researchers concluded that due to its low specificity, the ADAM questionnaire cannot be used as a surrogate for serum FT testing for the identification of androgen deficiency. In another study, Blümel et al. [19] identified 78 out of 96 men (81.3%) as LOH according to the ADAM questionnaire, but available testosterone confirmed the LOH diagnosis in only 27 cases (28.1%), resulting in a sensitivity of 83.3% and specificity of 19.7%. These authors found a low diagnosis efficiency. Although Chu et al. [22] evaluated the use of the ADAM questionnaire in Chinese men, there was no study addressing the efficiency of the AMS scale in a Chinese population. In our study, the AMS scale had both low sensitivity and specificity for detecting LOH in Chinese men. Regarding the ADAM questionnaire, it had relatively high sensitivity but very low specificity. It is necessary to illustrate that certain factors can influence the results of these two questionnaires, such as chronic diseases, depressive disorder and stress. Depression, which is common among elderly people in modern society, was found to be associated with the AMS questionnaire [23]. Thus, it should be noted that neither the AMS scale nor the ADAM questionnaire can be regarded as a suitable screening tool to replace biochemical methods of identifying LOH in the Chinese population.

In summary, our study analyzed the applicability of the AMS scale and ADAM questionnaire in a Chinese population, and we found that the hormone levels of FT, LH, FSH, SHBG and BT were correlated with both the AMS scale and ADAM questionnaire. However, due to the low sensitivity and specificity of the AMS scale and the relatively high sensitivity but low specificity of the ADAM questionnaire in the diagnosis of LOH, these two questionnaires were not suitable screening tools for the Chinese population. It is necessary to provide a new and robust questionnaire that is applicable to the Chinese population, combined with physical and biochemical work-ups, to detect LOH in clinical practice.

Declaration of interest

The authors report no declarations of interest.

The project was supported by the Major Scientific Research Proposal of the Science and Technology Commission of Shanghai Municipality (No. 09DJ1400400).