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ORIGINAL RESEARCH—ENDOCRINOLOGY The Impact of Androgen Receptor CAG Repeat Polymorphism on Andropausal Symptoms in Different Serum Testosterone Levels jsm_2672
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Chia-Chu Liu, MD,*†‡§ Yung-Chin Lee, MD,*†‡ Chii-Jye Wang, MD, PhD,*† Hsin-Chih Yeh, MD,*‡¶ Wei-Ming Li, MD,*‡§ Wen-Jeng Wu, MD, PhD,*†** Chun-Nung Huang, MD, PhD,*† Bo-Ying Bao, PhD,†† Chun-Hsiung Huang, MD, PhD,*† and Shu-Pin Huang, MD, PhD*† *Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; † Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; ‡ Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; §Pingtung Hospital, Department of Health, Executive Yuan, Pingtung, Taiwan; ¶Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan; **Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; ††Department of Pharmacy, China Medical University, Taichung, Taiwan DOI: 10.1111/j.1743-6109.2012.02672.x
ABSTRACT
Introduction. In addition to a depletion of androgen, attenuated action of androgen receptor (AR) might also contribute to andropausal symptoms. Aim. To evaluate the interaction of AR cytosine adenine guanine (CAG) repeat polymorphism and serum testosterone levels and their effect on andropausal symptoms in aging Taiwanese men. Methods. From August 2007 to April 2008, a free health screening for men older than 40 years was conducted by a medical center in Kaohsiung City, Taiwan. All participants received physical examination, answered questionnaires to collect their demographic information and medical histories, completed the Androgen Deficiency in the Aging Male (ADAM) questionnaire, and provided 20-cm3 whole blood samples for biochemical and genetic evaluation. Main Outcome Measures. The ADAM questionnaire was used to evaluate andropausal symptoms. Serum albumin, total testosterone (TT), and sex hormone-binding globulin levels were measured. Free testosterone level was calculated. AR gene CAG repeat polymorphism was determined by direct sequencing. Results. Seven hundred two men with the mean age of 57.2 ⫾ 6.5 years were included. There was no significant association between TT levels and the distribution of AR CAG repeat polymorphism. When TT levels were above 340 ng/dL, subjects with AR CAG repeat lengths ⭌25 showed significantly higher risk of developing andropausal symptoms, as compared with those with AR CAG repeat lengths ⬉22 (P = 0.006), but this was not observed when TT levels were 340 ng/dL or below. Age and number of comorbidities were also independent risk factors for andropausal symptoms. Conclusion. In subjects with normal TT concentration, those with longer AR CAG repeat lengths have a higher risk of developing andropausal symptoms. Age and number of comorbidities can also influence the appearance of andropausal symptoms. In clinical practice, a multifactorial approach to evaluate andropausal symptoms and the interactions between those risk factors is suggested. Liu C-C, Lee Y-C, Wang C-J, Yeh H-C, Li W-M, Wu W-J, Huang C-N, Bao B-Y, Huang C-H, and Huang S-P. The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in different serum testosterone levels. J Sex Med 2012;9:2429–2437. Key Words. Testosterone; Androgen Receptor; CAG Repeat Polymorphism; Andropause; Hypogonadism; Genetic Evaluation of Testosterone Deficiency Syndrome
© 2012 International Society for Sexual Medicine
J Sex Med 2012;9:2429–2437
2430 Introduction
A
ging in men, as in women, is accompanied by the appearance of many somatic and psychological symptoms and the decline of physiological function. These conditions may be attributed to aging-related decline in serum androgen levels, which is termed “andropause” or “late-onset hypogonadism” [1,2]. Previous studies have shown that serum testosterone levels will decline between 0.4% and 2.6% per year in men after 40 [3,4]. The clinical signs and symptoms suggestive of andropause or late-onset hypogonadism include diminished sexual desire and erectile function, depression, lethargy, osteoporosis, regression of secondary sexual characteristics, and loss of muscle mass and/or strength. Other possible sequelae may include diminished interest in activities, sleep disturbance, deteriorating work performance, and inability to concentrate [1,5]. However, in addition to a depletion of androgen, attenuated action of androgen receptor (AR) can also contribute to the symptoms of male hypogonadism or andropause [6]. The effects of androgen on its target cells are mediated through AR, a ligand-dependent nuclear transcription factor [7,8]. The first exon of the AR gene, encoding the entire N-terminal transactivation domain, contains a polymorphic CAG trinucleotide repeat sequence. This repeat is translated into a polyglutamine stretch in the receptor protein. Normally, the number of CAG repeats varies between 9 and 37 [7–9]. Previous in vitro studies have found that the number of CAG repeats is inversely associated with the transcriptional activity of androgen-dependent genes and hence with androgen effects in target tissues [10,11]. Because AR CAG repeat polymorphism can modulate the effects of circulating androgens, it may relate to variations of androgenicity and clinical picture of andropause or late-onset hypogonadism in men [6–8,12,13]. The aim of this study is to evaluate the interaction of AR CAG repeat polymorphism and serum testosterone levels and their effect on andropausal symptoms in aging Taiwanese men. Methods
From August 2007 to April 2008, a free health screening for men older than 40 years was conducted by a medical center in Kaohsiung City, Taiwan [14]. The screening was open to the general male population living in Kaohsiung City. J Sex Med 2012;9:2429–2437
Liu et al. Men who had current malignancy, liver cirrhosis or major psychiatric disorder, or who were using hormones, anti-androgen treatment, antifungal drugs, or steroidal agents were excluded. The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital, and all subjects provided informed consent before their participation.
Clinical Data Collection All participants were interviewed by trained researchers using a structured questionnaire to collect demographic information and detailed medical histories, especially diabetes mellitus, hypertension, hyperlipidemia, cardiovascular disease, stroke, and spinal cord injury. Questions regarding smoking and alcohol use were also included [14]. We also assessed andropausal symptoms in each participant using the Androgen Deficiency in the Aging Male (ADAM) questionnaire [14,15]. The ADAM questionnaire is a 10-item screening tool for identifying androgen deficiency in aging men. If a participant responded affirmative to decreased libido or strength of erection, or gave positive response to any three of the nonspecific questions including fatigability, decreased muscle strength, mood change, and loss of height, he was considered as having andropausal symptoms [14,15]. Blood pressure, body weight (kilogram), and height (centimeter) were also measured. Body mass index (BMI [kilogram per square meter]) was calculated as body weight divided by the square of body height. Normal weight, overweight, and obesity were defined as a BMI of less than 24, 24 to less than 27, and 27 or higher, respectively, according to the Taiwanese definition [14,16]. Hormone Analysis All participants had nonfasting 20-cm3 blood samples drawn between 8:00 and 11:00 am on the day of the 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, MN, USA), which had an interassay coefficient of variation (CV) of 3.6% and an intra-assay CV of 2.2% [14,17]. TT levels (detectable range: 10– 1,600 ng/dL; interassay CV of 8.4%, and intraassay CV of 5.2%) and SHBG levels (detectable range: 0.2–180 nmol/L; interassay CV of 4.8%,
AR CAG Repeat Polymorphism and Andropausal Symptoms and intra-assay CV of 3.5%) were determined using a DPC Immulite analyzer (Diamond Diagnostics, Holliston, MA, USA) [14,17]. Free testosterone (FT) level was calculated according to the Vermeulen formula [14,17].
Genetic Analysis DNA was extracted from peripheral blood using the Purgene DNA Isolation Kit (Gentra System Inc., MN, USA). AR CAG repeat polymorphism was determined by the polymerase chain reaction (PCR) and direct sequencing with primers and conditions that had been described previously [18]. The PCR product was purified using the QIA quick gel extraction kit (Qiagen, Valencia, CA, USA) and sequenced directly using an automated DNA sequencer (ABI 377; Perkin-Elmer, Weiterstadt, Germany) [18]. To reconfirm the results of genotyping, we randomly selected 40 subjects (~5% of the study subjects) for regenotyping by direct sequencing; the results were 100% identical. Statistical Analysis Data were expressed as mean ⫾ standard deviation unless otherwise indicated. Serum TT levels and AR CAG repeat lengths were examined as tertiles based on the entire population. Qualitative variables were compared using the chi-square test or Fisher’s exact test. Logistic regression analyses were used to evaluate the impact of AR CAG repeat polymorphism on andropausal symptoms given different TT levels with and without considering other covariates. The Statistical Package for Social Sciences, version 12.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analyses. A P value of less than 0.05 was considered significant. Results
Of the 819 men participating in the health screening, 117 subjects were excluded due to current malignancies (14 cases), current use of medications that would interfere with the measurement of natural testosterone levels (34 cases), and incomplete evaluation (69 cases), leaving 702 subjects with a mean age of 57.2 ⫾ 6.5 years (range: 43–87 years). The baseline characteristics and sociodemographic data of the study population are summarized in Table 1. Five hundred fourteen (73.2%) participants reported having andropausal symptoms according to the evaluation by ADAM questionnaire. The distribution of AR CAG repeat polymorphism in our study population is also
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shown in Figure 1. The mean value of AR CAG repeat length was 23.1 ⫾ 2.9 (median: 23, range: 11–32). The 33rd and 66th percentile values were set at 22 and 25 (Table 1). The relationships among TT levels, AR CAG repeat polymorphism, and andropausal symptoms are shown in Table 2. The 33rd and 66th percentile values of TT were set at the levels of 340 and 430 ng/dL, respectively. The prevalence of andropausal symptoms was found to decrease gradually as the TT levels increased, but the differences among the three TT groups did not reach statistical significance (P = 0.091). There was no significant difference in the distribution of AR CAG repeat polymorphisms among the three TT groups (P = 0.3). In the three TT groups, subjects with and without andropausal symptoms showed significant differences in their distribution of AR CAG repeat polymorphism in TT levels of 340– 430 and above 430 ng/dL, but not in TT of 340 ng/dL or below. The impact of AR CAG repeat polymorphism on andropausal symptoms in subjects with TT of 340 ng/dL or below and subjects with TT level above 340 ng/dL is shown in Tables 3 and 4. After considering other covariates including age, body size, number of comorbidities, smoking, alcohol drinking, and FT levels, AR CAG repeat polymorphism was found to be an independent predictor for andropausal symptoms in subjects with TT level above 340 ng/dL, but not in subjects with TT level of 340 ng/dL or below. When TT level was above 340 ng/dL, subjects with AR CAG repeat lengths of 25 or above had significantly higher risk of developing andropausal symptoms, compared with those with AR CAG repeat lengths of 22 or below (adjusted odds ratio [OR]: 2.06; 95% confidence interval [CI]: 1.23–3.47, P = 0.006). Furthermore, age and number of comorbidities were also independent risk factors for the development of andropausal symptoms in subjects with TT level above 340 ng/dL. In subjects with TT level of 340 ng/dL or below, only age, body size, and number of comorbidities were marginally significant predictors for andropausal symptoms. We also performed the sensitivity test to divide AR CAG repeat lengths into quartiles (ⱕ21, 22–23, 24–25, and ⱖ26) and found that subjects with AR CAG repeat lengths of 26 or above still had significantly higher risk of developing andropausal symptoms, compared with those with AR CAG repeat lengths of 21 or below in subjects with TT level above 340 ng/dL (adjusted OR: 2.17; 95% CI: 1.10–4.23, P = 0.026). The results J Sex Med 2012;9:2429–2437
2432 Table 1
Liu et al. Baseline characteristics of study population (N = 702)
Parameter Age, year Age groups 40–49 years 50–59 years 60–69 years ⭌70 years BMI (kg/m2) BMI groups Normal weight (BMI < 24) Overweight (24 < BMI ⬉ 27) Obesity (BMI > 27) Diabetes mellitus Hypertension Hyperlipidemia Cardiovascular disease Stroke Spinal cord injury Other systemic diseases The number of comorbidities 0 1 ⱖ2 Current smoking Current alcohol drinking Andropausal symptoms Endocrinologic Total testosterone (ng/dL) Free testosterone (ng/dL) SHBG (nmol/L) Albumin (g/dL) CAG repeat length ⬉22 (tertile 1) 23–24 (tertile 2) ⭌25 (tertile 3)
N (%)
110 405 147 40
Mean ⫾ SD
Range
57.2 ⫾ 6.5
43–87
24.6 ⫾ 2.7
17.1–34.5
389.4 ⫾ 107.6 6.6 ⫾ 2.7 48.8 ⫾ 23.9 4.4 ⫾ 0.2 23.1 ⫾ 2.9
52.0–823 0.2–28.6 6.9–164 3.6–5.0 11–32
(15.7) (57.7) (20.9) (5.7)
318 251 133 63 188 99 60 11 24 31
(45.3) (35.8) (18.9) (9.0) (26.8) (14.1) (8.5) (1.6) (3.4) (4.4)
371 221 110 95 96 514
(52.8) (31.5) (15.7) (13.5) (13.7) (73.2)
318 (45.3) 174 (24.8) 210 (29.9)
CAG = cytosine adenine guanine; BMI = body mass index; SD = standard deviation; SHBG = sex hormone-binding globulin
of AR CAG repeat lengths examined as tertiles and quartiles had similar trend. Discussion
In a sample of aging Taiwanese men, there was no significant association between TT levels and the distribution of AR CAG repeat polymorphism (Table 2). However, subjects with and without andropausal symptoms showed significant differences in the distribution of AR CAG repeat polymorphism when TT level was above 340 ng/dL, but not when TT was 340 ng/dL or below (Table 2). In the past, the diagnosis of hypogonadism has always been constrained by strict definitions of thresholds of serum androgen concentrations. The most widely accepted parameter for the diagnosis of hypogonadism is the measurement of serum TT level. Some studies have proposed that a TT level below 300 ng/dL, measured in the morning, can be considered a threshold for hypogonadism [19,20]. Others have suggested that TT level J Sex Med 2012;9:2429–2437
above 12 nmol/L (346 ng/dL) does not require testosterone substitution [1,21]. However, the level of androgen considered normal or sufficient for health is unknown and may vary among individuals and in different tissues of the same person. There is also no clear testosterone threshold associated with symptomatic hypogonadism. In a study of 434 aging male patients who presented with various andropausal symptoms, prevalence of loss of libido or loss of vigor increased below TT level of 15 nmol/L (433 ng/dL), whereas depressive mood was significantly more present in TT level below 10 nmol/L (288 ng/dL) and erectile dysfunction only below TT level of 8 nmol/L (231 ng/dL) [22]. In our study population, we did not find a significant difference of the prevalence of andropausal symptoms among three TT levels (Table 2). Contradictory results of the association between the appearance of andropausal symptoms and serum testosterone levels were also found in previous studies [23–25]. This may be in part due to variation of the study population and
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AR CAG Repeat Polymorphism and Andropausal Symptoms
Figure 1 The distribution of androgen receptor CAG repeat polymorphism in study population. CAG = cytosine adenine guanine.
also to the fact that testosterone effects are modified by the AR gene and especially by AR CAG repeat polymorphism [9,26,27]. Canale and his colleagues reported that hypoandrogenic Italian men have a shift in the frequency distribution toward longer CAG repeat length compared with normal controls (mean number of CAG repeat length: 24.0 ⫾ 2.9 vs. 21.5 ⫾ 1.7, P < 0.0001). However, serum TT levels were not different between those two groups (15.3 ⫾ 7.3 vs. 15.3 ⫾ 3.8 nmol/L, P = 0.89) [26]. They suggested that given the same amount of circulating testosterone, the final net androgenic phenotypical effect would be determined by the AR polymorphism [26]. Table 2
In our study, AR CAG repeat polymorphism was found to be an independent predictor for andropausal symptoms in subjects with TT level above 340 ng/dL (Table 4). However, this was not found in subjects with TT of 340 ng/dL or below (Table 3). It is interesting to note that the TT level of 340 ng/dL is near a threshold (12 nmol/L) suggesting that testosterone substitution is not required below this level [1,21]. Testosterone levels within normal range can more or less saturate ARs. It has been shown that androgen effects reach a plateau at certain levels, presumably due to maximal binding of androgen to AR, which is probably tissue or symptom specific [8,28]. Just recently, a saturation model for prostate tissue in
TT levels, androgen receptor CAG repeat polymorphism, and andropausal symptoms
Numbers CAG repeat length (N, %) ⬉22 23–24 ⭌25 Andropausal symptoms Numbers (N, %) CAG repeat length (N, %) ⬉22 23–24 ⭌25 P value
TT ⬉ 340
340 < TT ⬉ 430
TT > 430
234
235
233
119 50 65 Yes 183
(50.8) (21.4) (27.8) (78.2)
92 (50.3) 40 (21.9) 51 (27.8) 0.93
No 51 (21.8) 27 (52.9) 10 (19.6) 14 (27.5)
97 64 74 Yes 169
(41.3) (27.2) (31.5) (71.9)
70 (41.4) 39 (23.1) 60 (35.5) 0.032
No 66 (28.1) 27 (40.9) 25 (37.9) 14 (21.2)
102 60 71 Yes 162
P value
(43.8) (25.7) (30.5) (69.5)
62 (38.3) 44 (27.2) 56 (34.5) 0.03
0.3
No 71 (30.5)
0.091
40 (56.4) 16 (22.5) 15 (21.1)
CAG = cytosine adenine guanine; TT = total testosterone
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Liu et al.
Table 3 The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in subject with total testosterone ⬉ 340 ng/dL
CAG repeat length (N, %) ⬉22 23–24 ⭌25 P for trend Age (decade) Body sizes Normal weight (BMI < 24) Overweight (24 ⬉ BMI < 27) Obesity (BMI ⭌ 27) P for trend Comorbidities None One Two or greater P for trend Smoking Alcohol drinking Free testosterone
Andropausal symptoms N = 183
No andropausal symptoms N = 51
OR
95% CI
P value
Adjusted OR
95% CI
P value
92 (50.3) 40 (21.9) 51 (27.8)
27 (52.9) 10 (19.6) 14 (27.5)
1 1.17 1.07
0.52–2.65 0.52–2.22
0.7 0.56
Ref 1.23 1.08
0.50–3.04 0.49–2.38
1.61
0.97–2.66
0.65 0.85 0.81 0.064
Ref 1.61 2.6
0.78–3.34 0.93–7.24
0.2 0.067 0.049
Ref 0.75 4.09
0.37–1.50 0.87–19.2
2.47 0.45 1.09
0.71–8.63 0.16–1.25 0.87–1.36
0.41 0.074 0.22 0.16 0.127 0.46
OR = odds ratio; CI = confidence interval; BMI = body mass index; CAG = cytosine adenine guanine
relation to testosterone concentration has been proposed [29]. Because AR CAG repeat polymorphism can moderate the effects of circulating testosterone by influencing the sensitivity of the AR, it can be related to variations of androgenicity in (apparently) eugonadal men and may cause the clinical picture of hypogonadism in the presence of normal TT concentrations [6,8]. The longer the length of CAG repeats, the less prominent the
androgen effect when individuals with similar TT concentrations are compared [6,8]. However, the symptoms assessed by ADAM questionnaire are unspecific to hypogonadism and can be multifactorial origin [21]. In addition to the variation of testosterone levels and the sensitivity of AR, chronic illness, stress, poor nutrition, and medication may produce andropausal-like symptoms and thus confound the diagnosis of late-onset
Table 4 The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in subject with total testosterone > 340 ng/dL
CAG repeat length (N, %) ⬉22 23–24 ⭌25 P for trend Age (decade) Body sizes Normal weight (BMI < 24) Overweight (24 ⬉ BMI < 27) Obesity (BMI ⭌ 27) P for trend Comorbidities None One Two or greater P for trend Smoking Alcohol drinking Free testosterone
Andropausal symptoms N = 331
No andropausal symptoms N = 137
OR
95% CI
P value
Adjusted OR
95% CI
P value
132 (39.9) 83 (25.1) 116 (35.0)
67 (48.9) 41 (29.9) 29 (21.2)
1 1.03 2.03
0.64–1.65 1.23–3.35
0.91 0.006
Ref 1.01 2.06
0.61–1.66 1.23–3.47
1.72
1.24–2.39
0.98 0.006 0.01 0.001
Ref 0.92 0.76
0.58–1.47 0.42–1.37
0.92 0.36 0.38
Ref 0.98 2.38
0.62–1.57 1.08–5.23
1.37 1.42 1.003
0.69–2.70 0.75–2.71 0.92–1.09
0.95 0.032 0.079 0.36 0.28 0.95
OR = odds ratio; CI = confidence interval; BMI = body mass index; CAG = cytosine adenine guanine
J Sex Med 2012;9:2429–2437
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AR CAG Repeat Polymorphism and Andropausal Symptoms hypogonadism or andropause [27,30]. Our findings also support this view. In multivariate analyses, age and number of comorbidities are also independent predictors for andropausal symptoms. In subjects with TT of 340 ng/dL or below, body size was a marginally significant predictor for andropausal symptoms. In clinical practice, a multifactorial approach to evaluate andropausal symptoms and the interactions between those risk factors is suggested. In addition, we did not find the association between TT levels and the distribution of AR CAG repeat polymorphism, which is consistent with previous observations of several studies [27,31–33]. However, Huhtaniemi et al. reported positive associations between the length of AR CAG repeat and TT and FT levels in a sample of 2,878 aging men recruited from eight European countries. They suggested that this may be the result of compensatory upregulation of TT in subjects with longer length of AR CAG repeat [34]. The contradictory results might be due to the selection of study populations. In men with disturbed hypothalamic– pituitary–gonadal feedback mechanisms, such as in those with late-onset hypogonadism or metabolic syndrome, the compensatory regulation of testosterone levels by the length of AR CAG repeat might not exist [27]. There are some limitations in this study. First, our data were based on community-dwelling men participating in a free health screening. Although the screening was open to the general male population, some selection bias may exist. Other large population-based studies may be needed to confirm our preliminary results. Second, the ADAM questionnaire may not be a good instrument to assess andropausal symptoms due to its low specificity [35]. Other instruments such as the Aging Males’ Symptoms Scale [35,36] or the Massachusetts Male Aging Study questionnaire [35,37] may also be used to confirm our results.
to evaluate andropausal symptoms and the interactions between those risk factors is suggested. Acknowledgements
This study was supported by grants from the Taiwan National Science Council (NSC 98-2314-B-037-030MY3; NSC99-2314-B-037-022-MY3) and Kaohsiung Medical University Hospital (KMUH98-8R10; KMUH99-9R13; KMUH99-9R14). We thank Ms. Chao-Shih Chen for her help to hold the healthy screening and Neogene Biomedicals Corp. for their technical support on direct sequencing. Corresponding Author: Shu-Pin Huang, MD, Department of Urology, Kaohsiung Medical University Hospital, No. 100, TzYou 1st Road, Kaohsiung City 807, Taiwan. Tel: +886-7-3121101-6694; Fax: +886-73211033; E-mail:
[email protected] Conflict of Interest: None. Statement of Authorship
Category 1 (a) Conception and Design Chia-Chu Liu; Yung-Chin Lee; Shu-Pin Huang (b) Acquisition of Data Chii-Jye Wang; Hsin-Chih Yeh; Wei-Ming Li; Wen-Jeng Wu; Chun-Nung Huang; Chun-Hsiung Huang (c) Analysis and Interpretation of Data Chia-Chu Liu; Bo-Ying Bao; Shu-Pin Huang
Category 2 (a) Drafting the Article Chia-Chu Liu; Yung-Chin Lee; Shu-Pin Huang (b) Revising It for Intellectual Content Chii-Jye Wang; Hsin-Chih Yeh; Wei-Ming Li; Wen-Jeng Wu; Chun-Nung Huang; Bo-Ying Bao; Shu-Pin Huang
Category 3 (a) Final Approval of the Completed Article Chia-Chu Liu; Yung-Chin Lee; Chii-Jye Wang; Hsin-Chih Yeh; Wei-Ming Li; Wen-Jeng Wu; Chun-Nung Huang; Bo-Ying Bao; Chun-Hsiung Huang; Shu-Pin Huang
Conclusion
In a sample of aging Taiwanese men, there was no significant association between TT levels and the distribution of AR CAG repeat polymorphism. In subjects with normal TT concentrations, those with longer AR CAG repeat polymorphisms are at a higher risk of developing andropausal symptoms. Furthermore, age and number of comorbidities can also influence the appearance of andropausal symptoms. In clinical practice, a multifactorial approach
References 1 Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morley JE, Schulman C, Wang C, Weidner W, Wu FC. Investigation, treatment and monitoring of late-onset hypogonadism in males. ISA, ISSAM, and EAU recommendations. Eur Urol 2005;48:1–4. 2 Comhaire FH. Andropause: Hormone replacement therapy in the ageing male. Eur Urol 2000;38:655–62. 3 Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-
J Sex Med 2012;9:2429–2437
2436
4
5
6
7
8 9
10
11
12
13
14
15
16
17
18
19 20
aged men: Longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002;87:589–98. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–31. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Testosterone therapy in adult men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2006;91:1995–2010. Buvat J, Maggi M, Gooren L, Guay AT, Kaufman J, Morgentaler A, Schulman C, Tan HM, Torres LO, Yassin A, Zitzmann M. Endocrine aspects of male sexual dysfunctions. J Sex Med 2010;7:1627–56. Zitzmann M. The role of the CAG repeat androgen receptor polymorphism in andrology. Front Horm Res 2009;37: 52–61. Zitzmann M. Pharmacogenetics of testosterone replacement therapy. Pharmacogenomics 2009;10:1341–9. Harkonen K, Huhtaniemi I, Makinen J, Hubler D, Irjala K, Koskenvuo M, Oettel M, Raitakari O, Saad F, Pollanen P. The polymorphic androgen receptor gene CAG repeat, pituitarytesticular function and andropausal symptoms in ageing men. Int J Androl 2003;26:187–94. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994;22:3181–6. Beilin J, Ball EM, Favaloro JM, Zajac JD. Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: Specificity in prostate and non-prostate cell lines. J Mol Endocrinol 2000;25:85–96. Giagulli VA, Triggiani V, Carbone MD, Corona G, Tafaro E, Licchelli B, Guastamacchia E. The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism. J Sex Med 2011;8:3471–8. Schneider G, Nienhaus K, Gromoll J, Heuft G, Nieschlag E, Zitzmann M. Sex hormone levels, genetic androgen receptor polymorphism, and anxiety in ⱖ50-year-old males. J Sex Med 2011;8:3452–64. Liu CC, Wu WJ, Lee YC, Wang CJ, Ke HL, Li WM, Hsiao HL, Yeh HC, Li CC, Chou YH, Huang CH, Huang SP. The prevalence of and risk factors for androgen deficiency in aging Taiwanese men. J Sex Med 2009;6:936–46. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry HM, 3rd. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49:1239–42. Pan WH, Flegal KM, Chang HY, Yeh WT, Yeh CJ, Lee WC. Body mass index and obesity-related metabolic disorders in Taiwanese and US whites and blacks: Implications for definitions of overweight and obesity for Asians. Am J Clin Nutr 2004;79:31–9. Liu CC, Huang SP, Li WM, Wang CJ, Chou YH, Li CC, Huang CH, Wu WJ. Relationship between serum testosterone and measures of benign prostatic hyperplasia in aging men. Urology 2007;70:677–80. Huang SP, Chou YH, Chang WS, Wu MT, Yu CC, Wu T, Lee YH, Huang JK, Wu WJ, Huang CH. Androgen receptor gene polymorphism and prostate cancer in Taiwan. J Formos Med Assoc 2003;102:680–6. Testosterone replacement therapy for male aging: ASA position statement. J Androl 2006;27:133–4. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: The HIM study. Int J Clin Pract 2006;60:762–9.
J Sex Med 2012;9:2429–2437
Liu et al. 21 Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC. Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. Eur Urol 2009;55: 121–30. 22 Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006;91: 4335–43. 23 Spetz AC, Palmefors L, Skobe RS, Stromstedt MT, Fredriksson MG, Theodorsson E, Hammar ML. Testosterone correlated to symptoms of partial androgen deficiency in aging men (PADAM) in an elderly Swedish population. Menopause 2007;14:999–1005. 24 Miwa Y, Kaneda T, Yokoyama O. Correlation between the Aging Males’ Symptoms Scale and sex steroids, gonadotropins, dehydroepiandrosterone sulfate, and growth hormone levels in ambulatory men. J Sex Med 2006;3:723–6. 25 Emmelot-Vonk MH, Verhaar HJ, Nakhai-Pour HR, Grobbee DE, van der Schouw YT. Low testosterone concentrations and the symptoms of testosterone deficiency according to the Androgen Deficiency in Ageing Males (ADAM) and Ageing Males’ Symptoms rating scale (AMS) questionnaires. Clin Endocrinol (Oxf) 2011;74:488–94. 26 Canale D, Caglieresi C, Moschini C, Liberati CD, Macchia E, Pinchera A, Martino E. Androgen receptor polymorphism (CAG repeats) and androgenicity. Clin Endocrinol (Oxf) 2005;63:356–61. 27 Schneider G, Nienhaus K, Gromoll J, Heuft G, Nieschlag E, Zitzmann M. Aging males’ symptoms in relation to the genetically determined androgen receptor CAG polymorphism, sex hormone levels and sample membership. Psychoneuroendocrinology 2010;35:578–87. 28 Bhasin S, Woodhouse L, Casaburi R, Singh AB, Bhasin D, Berman N, Chen X, Yarasheski KE, Magliano L, Dzekov C, Dzekov J, Bross R, Phillips J, Sinha-Hikim I, Shen R, Storer TW. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab 2001;281:E1172– 81. 29 Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: The saturation model and the limits of androgen-dependent growth. Eur Urol 2009;55: 310–20. 30 Tancredi A, Reginster JY, Luyckx F, Legros JJ. No major month to month variation in free testosterone levels in aging males. Minor impact on the biological diagnosis of “andropause”. Psychoneuroendocrinology 2005;30:638–46. 31 Goutou M, Sakka C, Stakias N, Stefanidis I, Koukoulis GN. AR CAG repeat length is not associated with serum gonadal steroids and lipid levels in healthy men. Int J Androl 2009;32:616–22. 32 T’Sjoen GG, De Vos S, Goemaere S, Van Pottelbergh I, Dierick M, Van Heeringen C, Kaufman JM. Sex steroid level, androgen receptor polymorphism, and depressive symptoms in healthy elderly men. J Am Geriatr Soc 2005;53: 636–42. 33 Van Pottelbergh I, Lumbroso S, Goemaere S, Sultan C, Kaufman JM. Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men. Clin Endocrinol (Oxf) 2001;55: 659–66. 34 Huhtaniemi IT, Pye SR, Limer KL, Thomson W, O’Neill TW, Platt H, Payne D, John SL, Jiang M, Boonen S, Borghs H, Vanderschueren D, Adams JE, Ward KA, Bartfai G, Casanueva F, Finn JD, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Silman AJ, Wu FC.
AR CAG Repeat Polymorphism and Andropausal Symptoms Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. J Clin Endocrinol Metab 2009;94:277–84. 35 Morley JE, Perry HM, 3rd, Kevorkian RT, Patrick P. Comparison of screening questionnaires for the diagnosis of hypogonadism. Maturitas 2006;53:424–9.
2437
36 Heinemann LA. Aging Males’ Symptoms scale: A standardized instrument for the practice. J Endocrinol Invest 2005;28:34–8. 37 Smith KW, Feldman HA, McKinlay JB. Construction and field validation of a self-administered screener for testosterone deficiency (hypogonadism) in ageing men. Clin Endocrinol (Oxf) 2000;53:703–11.
J Sex Med 2012;9:2429–2437
