J C E M A d v a n c e s i n G e n e t i c s — E n d o c r i n e O N L I N E R e s e a r c h Androgen Receptor CAG Repeat Length Is Associated With Body Fat and Serum SHBG in Boys: A Prospective Cohort Study Annette Mouritsen, Casper P. Hagen, Kaspar Sørensen, Lise Aksglaede, Mikkel G. Mieritz, Katharina M. Main, Kristian Almstrup, Ewa Rajpert-De Meyts, and Anders Juul Department of Growth and Reproduction, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, 2100 Copenhagen, Denmark Background: Longer androgen receptor gene CAG trinucleotide repeats, AR (CAG)n, have been associated with reduced sensitivity of the androgen receptor (AR) in vitro as well as in humans. Furthermore, short AR (CAG)n have been associated with premature adrenarche. CD R Objective: The aim of the study was to evaluate associations between the AR (CAG)n polymorphism and development of pubic hair, levels of androgens, and body fat content in healthy boys. da p or Methods: A longitudinal study of 78 healthy boys (age 6.2–12.4 years at inclusion) from the COPENHAGEN Puberty Study was conducted with clinical examinations and blood samples drawn every 6 months. The AR (CAG)n length was established by direct DNA sequencing and reproductive hormones were measured in serum by standardized analyses. pi aa ut or iza Results: Median AR (CAG)n length was 22 (range, 17–30). Before puberty (at 10 years of age), boys with long CAG repeats (CAG ⱖ24) had lower levels of SHBG (88 vs 125 nmol/L) (P ⬍ .05) and a nonsignificant trend toward higher median skinfold thickness (41 vs 31 mm) (P ⫽ .06) compared with boys with an average number of CAG repeats (CAG 21–23). In contrast, the inverse association was observed at puberty (at 12 years of age) in boys with short CAG repeats (CAG 17–20) (P ⬍ .05). Serum levels of LH and testosterone (at 12 years) were significantly higher in boys with long CAG repeats compared with boys with an average number of CAG repeats (P ⫽ .05). Co Conclusion: The observed associations between AR (CAG)n and peripubertal fat accumulation and serum SHBG concentrations indicate that this genetic polymorphism may influence the androgendependent fine-tuning of metabolic and reproductive factors at a young age. (J Clin Endocrinol Metab 98: E605–E609, 2013) ndrogens mediate their effects primarily through activation of the androgen receptor (AR). The X-chromosomal AR contains a highly polymorphic region with variable number of CAG repeats, (CAG)n, which encodes a polyglutamine tract in the N-terminal transactivation domain of the receptor (1). A negative linear association between AR sensitivity and CAG repeat length has been proposed based on the presentation of partial androgen resistance in men with spinobulbar dystrophy (Kennedy syndrome) caused by AR CAG repeat lengths greater than A 40 (2), supported by 2 in vitro studies (3, 4). Subsequently, numerous epidemiological studies have associated longer AR (CAG)n, with disorders linked to reduced androgen activity, eg, male subfertility (5). However, whether the association between (CAG)n and androgen receptor activity is linear seems to be contentious (6, 7). A recent in vitro study investigated transcriptional activity of AR carrying different (CAG)n within the normal range and observed reduced AR activity in cells transfected with AR containing both shorter (16) and longer ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2013 by The Endocrine Society doi: 10.1210/jc.2012-3778 Received November 1, 2012. Accepted December 28, 2012. First Published Online February 7, 2013 Abbreviations: AR, androgen receptor; BMI, body mass index; CV, coefficient of variation; DHEAS, dehydroepiandrosterone; TV, testicular volume. J Clin Endocrinol Metab, March 2013, 98(3):E605–E609 jcem.endojournals.org 25/04/2014 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 24 April 2014. at 14:37 For personal use only. No other uses without permission. . All rights reserved. E605 E606 Mouritsen et al Androgen Receptor CAG Repeats and Body Fat in Boys J Clin Endocrinol Metab, March 2013, 98(3):E605–E609 ation (CVs) were less than 5% in both gonadotropin assays. Testosterone levels were measured with the DPC Coat-A-Count radioimmunoassay kit (Diagnostic Products, Los Angeles, California) with detection limit of 0.23 nmol/L and the intra- and interassay CVs were 7.6% and 8.6%, respectively. DHEAS and androstenedione levels were measured by specific solid-phase, competitive chemiluminescent enzyme immunoassays (Immulite 2000; Siemens, Erlanger, Germany) with detection limits of 0.41 mol/L and 1.04 nmol/L, respectively. The intra- and interassay CVs were 6.3% to 7.1% and 7.8% to 10.2% and 7.1% to 10.8% and 11.0% to 14.9%, respectively. (28) CAG repeats compared with the medium-length (22) CAG allele, suggesting that the association between repeat length and AR activity is nonlinear (8). Short AR (CAG)n have been associated with premature adrenarche (9), and longer AR (CAG)n have been associated with earlier pubertal growth spurts in boys (10). However, it is not known whether the length of the AR (CAG)n is associated with age at pubertal onset and body fat accumulation in healthy boys. In this prospective cohort study of healthy boys followed during pubertal transition, we aimed to evaluate whether short and long AR (CAG)n, respectively, were associated with clinical and biochemical markers of androgen activity, ie, pubertal onset (gonadarche and pubarche), fat accumulation, and circulating testosterone, LH, SHBG, dehydroepiandrosterone (DHEAS), and ⌬4-androstenedione. Genotyping R Molecular analysis of the AR gene polymorphism was performed using genomic DNA purified from peripheral blood samples. The CAG repeat⫺containing part of exon 1 of the AR gene was amplified by nested PCR using 2 sets of primers in a single reaction, and the CAG repeat number was established by direct sequencing. The method has been validated in our laboratory in a series of 116 fertile healthy Danish men, who had a mean of 21.8 and a median of 21 (range 14 –33) CAG repeats (6). The median (P ⫽ .05) and distribution (P ⫽ .74) did not differ from the current study. CD Subjects and Methods da p Statistical analysis Data for CAG distribution are presented as median and range; all other data are presented as median and 25th and 75th percentiles. Nonparametric Mann-Whitney test was used to compare boys with short or long CAG repeats with boys with medium CAG repeat length according to hormone levels, body composition (body mass index [BMI] and sum of 4 skinfolds) and hormone levels. Pearson correlation was used to estimate correlations between CAG length and SHBG or body fat. Comparisons of distributions between groups were performed by the Levene test. To counteract the problem of multiple comparisons, we could have used the Bonferroni correction. The method is conservative and assumes that all 3 comparisons between the 3 groups in the study are conducted. Because only 2 comparisons between groups (low vs medium and high vs medium) were conducted, our P values are not corrected with the Bonferroni correction (k ⫻ [k ⫺ 1]/2). All statistical analyses were carried out using SPSS software (version 19; SPSS, Inc, Chicago, Illinois). aa Clinical examination ut or iza This analysis was not the primary purpose of the study, but a secondary analysis of a total of 78 healthy Danish boys from the longitudinal part of the COPENHAGEN Puberty Study (11, 12), which were included with clinical examinations and blood samples drawn every 6 months from 2006 to 2011. Some of these hormones have reported on previously (13, 14). Participants of non-Caucasian origin or with no blood sample were excluded from analyses of the present substudy. or Subjects Co pi Pubertal stages were evaluated by clinical examination according to Marshall and Tanner. Testicular volume (TV) was measured by palpation to the nearest milliliter using the Prader orchidometer. In the case of a discrepancy between the left and right side, the largest measurement was used for classification. Assessment of pubic hair staging was done by visual inspection. Pubertal onset was defined as TV ⬎ 3 mL in boys. All evaluations of puberty in the boys were done by 1 of 3 male pediatricians. Age at onset of pubic hair (PH2⫹) was assigned as the mean age between ages at first examination in pubic hair stage 2 and the latest examination in pubic hair stage 1. The same method was used to determine age at testicular enlargement (TV ⬎ 3 mL). In 4 of the boys, the age at PH2⫹ was measured with 6 months accuracy because 12 months elapsed between examinations. Skinfolds were measured at the biceps, triceps, subscapular, and iliac crest on the left side of the body using a Holtain skinfold caliper calibrated to 0.2 mm (Harpenden, British Indicators Ltd, London, United Kingdom). Hormone analyses Blood samples were drawn from an antecubital vein between 800 and 1000 hours. They were clotted and centrifuged, and serum was stored immediately at ⫺20°C until hormone analyses were performed. Serum LH was measured by time-resolved immunofluorometric assays (Delfia; PerkinElmer, Waltham, Massachusetts) with detection limits of 0.06 and 0.05 IU/L for FSH and LH, respectively. Intra- and interassay coefficients of vari- Ethical considerations The COPENHAGEN Puberty Study was approved by the local ethics committee (KF 01 282214 and V200.1996/90). The study is registered in www.ClinicalTrials.gov (identifier NCT01411527). Results The median AR (CAG)n was 22 (range 17–30) in the 78 healthy boys (Figure 1A). The boys were divided in quartiles (Q1–Q4), according to the length of CAG repeats: short (Q1), ⱕ20 CAG repeats (25 boys); median (Q2 ⫹ Q3), 21–23 CAG repeats (27 boys); and long (Q4), ⱖ24 CAG repeats (26 boys). In prepuberty (measured at 10 years of age), the median sum of skinfolds in boys with long CAG repeats was 25/04/2014 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 24 April 2014. at 14:37 For personal use only. No other uses without permission. . All rights reserved. J Clin Endocrinol Metab, March 2013, 98(3):E605–E609 14 6 8 25 6 4 a, b 2 17 18 19 20 21 22 23 24 25 26 27 29 30 CAG repeats (number) 3 a 2 b 20 15 10 5 1 0 0 8 9 10 11 12 13 14 C 8 9 10 11 12 13 14 D 300 120 a 200 150 100 a 80 R Sum of fou ur skinfolds (mm) 100 60 CD b 250 SHBG (nmol/l) 30 10 0 4 E607 40 or LH (IU/l) 5 B 12 Testosterrone (nmol/l) 7 Boys (number) A jcem.endojournals.org 20 da p 50 0 0 9 10 11 12 Age (years) 13 8 14 9 iza 8 10 11 12 13 14 Age (years) aa ut or Figure 1. Individual assessments of body fat accumulation and serum hormone levels in the group of boys with ⱕ20 CAG repeats (blue lines) 21– 23 CAG repeats (black lines), and ⱖ24 CAG repeats (red lines). Statistical significance representing P ⬍ .05 are given as a (short CAG compared with medium-length CAG) and b (long CAG compared with medium-length CAG), respectively. A, Levels of LH according to age. B, Levels of testosterone according to age. C, Levels of SHBG according to age. D, Sum of 4 skinfolds according to age. Co pi 41 mm (25th–75 percentile, 31–55 mm) compared with 31 mm in boys with medium-length CAG repeats (23–39 mm) (P ⫽ .06) (Figure 1D), and boys with long CAG repeats had lower SHBG (88 nmol/L [79 –120 nmol/L]) compared with that of boys with medium-length CAG repeats (125 nmol/L [94 –156 nmol/L]; P ⫽ .042) (Figure 1C). The inverse association was observed in boys with short CAG repeats, although not statistically significant at 10 years of age, but at 12 years of age, the boys with short CAG repeats had statistically significant less body fat compared with both boys with medium-length CAG repeats, as both BMI and skinfold thickness were lower and SHBG was higher in puberty (all P ⬍ .05) (Table 1). A positive linear correlation was observed between CAG length and skinfold thickness (r ⫽ 0.315 at 10 years and r ⫽ 0.299 at 12 years; both P ⬍ .05) and a negative linear correlation between CAG length and SHBG (r ⫽ ⫺0.352 at 10 years and r ⫽ ⫺0.440 at 12 years, P ⬍ .05 and P ⫽ .068, respectively). A nonsignificant trend toward younger age at pubarche (11.4 vs 12.3) years was observed in the group of boys with long CAG repeats compared with the boys with mediumlength CAG repeats (Table 1). In puberty, the levels of LH (at 12 years of age) were significantly higher in boys with short as well as with long CAG repeats compared with those in boys with mediumlength CAG repeats (all P ⬍ .05). Testosterone (at 12 years of age) also was higher in boys with long CAG repeats compared with that in boys with medium-length CAG repeats (P ⬍ .05) (Table 1 and Figure 1, A and B). A large number of comparisons were conducted, and with a Bonferroni corrected P values statistically significant differences were observed for LH and skinfolds between boys with short CAG repeats and medium CAG repeats and for LH and testosterone between boys with long CAG repeats and boys with medium CAG repeats at 12 years of age. No significant association was observed between the length of CAG repeats and adrenal androgens, DHEAS and ⌬4-androstenedione. Discussion In this study of healthy Caucasian boys, we found a median of 22 CAG repeats in the AR gene, which was similar to the median (21) and distribution found in our previous study of 116 adult fertile men (6). Likewise, similar dis- 25/04/2014 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 24 April 2014. at 14:37 For personal use only. No other uses without permission. . All rights reserved. E608 Mouritsen et al Androgen Receptor CAG Repeats and Body Fat in Boys J Clin Endocrinol Metab, March 2013, 98(3):E605–E609 Table 1. Clinical and Biochemical Parameters in 78 Healthy Boys at 10, 11, and 12 Years of Age According to AR CAG Repeat Numbers Numbers of CAG Repeats 17–20 Median 25thⴚ75th Percentiles 138.7–148.4 15.8 –17.2 24 –35 107–162 0.01–2.11 0.6 –2.6 0.07– 0.12 ⬍0.21–⬍0.21 143.8 17.4 31 125 0.01 1.2 0.1 ⬍0.21 137.6 –145.4 16.2–19.1 23–39 94 –156 0.01–1.36 0.6 –1.4 0.04 – 0.09 ⬍0.21–⬍0.21 142.6 18.1 41 88a 0.01 1.6 0.1 ⬍0.21 137.4 –147.0 16.7–19.8 31–55 79 –120 0.01–1.23 1.2–2.2 0.04 – 0.27 ⬍0.21–⬍0.21 145.6 17.6 29 120 1.58 2.2 0.4a ⬍0.21 143.5–152.4 16.8 –18.6 25–36 93–134 0.01–2.58 0.8 –2.7 0.17–1.15 ⬍0.21– 0.81 148.1 17.1 35 94 0.01 1.5 0.1 ⬍0.21 142.8 –149.8 16.6 –19.6 27– 43 81–132 0.01– 0.81 0.9 –2.3 0.05– 0.56 ⬍0.21– 0.11 147.6 18.4 37 85 1.30 1.7 0.4 ⬍0.21 141.4 –152.8 17.2–19.5 30 –50 67–111 0.01–2.36 1.2–2.4 0.17– 0.94 ⬍0.21– 0.38 149.7 17.1a 28a 115a 1.76 2.6 1.3a 0.98 12.2 11.1 146.8 –156.8 15.6 –17.8 21–33 100 –135 0.01–3.22 1.4 –3.4 1.02–1.89 0.15–1.61 11.4 –12.7 10.8 –11.6 152.2 18.2 49 86 1.47 1.9 0.6 ⬍0.21 12.3 11.8 147.4 –155.6 17.4 –21.0 30 – 61 72–112 0.57–1.75 1.4 –2.4 0.45– 0.86 ⬍0.21– 0.82 11.2–12.7 10.6 –12.3 155.1 19.4 43 71 2.40 2.4 1.2a 2.2a 11.4 11.5 150.7–160.4 17.7–20.4 29 – 66 52–94 0.80 –3.51 1.8 –3.5 1.01–2.73 0.47– 8.25 10.6 –12.0 10.7–11.9 ut CD or da p or iza 140.2 16.9 29 131 0.61 1.4 0.1 ⬍0.21 R Median P ⬍ .05 compared with the medium–length group (CAG 21–23). pi a Median 24 –30 25thⴚ75th Percentiles aa At 10 y of age Height, cm BMI, kg/m2 Sum of skinfolds, mm SHBG, nmol/L Androstenedione, nmol/L DHEAS, mol/L LH, IU/L Testosterone, nmol/L At 11 y of age Height, cm BMI, kg/m2 Sum of skinfolds, mm SHBG, nmol/L Androstenedione, nmol/L DHEAS, mol/L LH, IU/L Testosterone, nmol/L At 12 y of age Height, cm BMI, kg/m2 Sum of skinfolds, mm SHBG, nmol/L Androstenedione, nmol/L DHEAS, mol/L LH, IU/L Testosterone, nmol/L Age at PH2⫹, y Age at TV ⬎3 mL, y 21–23 25thⴚ75th Percentiles Co tributions have been reported in other studies of Caucasian males (7, 15). We observed a nonlinear association between CAG repeat length and circulating LH and testosterone in early puberty. In contrast, the observed association between CAG repeat length and body fat (and SHBG) was linear. We found a greater accumulation of body fat (and lower serum levels of SHBG) in boys with long CAG repeats (within normal range), but the opposite was found in boys with short CAG repeats. These findings became statistically significant after the onset of pubic hair, ie, at the beginning of puberty, which suggests that androgens are involved in the physiological mechanisms. This suggestion is consistent with previous findings of higher body fat content in adult men with longer CAG repeats (16) and lower BMI or higher muscle mass in men with shorter CAG repeats (17). Conversely, one study reported a higher level of fat free mass in adult men with longer CAG, comparing 2 groups divided by the median (⬍22 and ⱖ22) (18). However, few studies of CAG repeats and body fat content in boys and adolescents exist. One study of ado- lescents reported a positive correlation between BMI and number of CAG repeats (9), whereas another study of boys from 13 years of age did not confirm such an association between body composition and CAG repeats (10). Our longitudinal findings are in line with the Dutch cross-sectional study of males (13–36 years of age), reporting an earlier pubertal growth spurt in boys with long CAG repeats but no association between CAG repeat length and final height (10). Thus, although AR (CAG)n seem to affect metabolism and reproductive factors in prepubertal boys, the effect of (CAG)n on androgen activity declines as the serum testosterone concentration increases after pubertal onset. Earlier fat accumulation in the boys with long CAG repeat length could be related to the decreased AR signaling in adipocytes, because a study of male AR knockout mice suggested that AR signaling in adipocytes protects against high-fat diet–induced obesity (19). A combination of elevated testosterone, which has been reported in some studies of adult men with long (CAG)n (18) and decreased SHBG (20), results in an increased level of free androgens. The increased level of free androgens 25/04/2014 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 24 April 2014. at 14:37 For personal use only. No other uses without permission. . All rights reserved. J Clin Endocrinol Metab, March 2013, 98(3):E605–E609 jcem.endojournals.org could reflect a compensatory mechanism due to decreased AR sensitivity in boys with long (CAG)n. Furthermore, long CAG repeat length might be associated with earlier pubarche. Limitations of the study are the small sample size and the performance of multiple comparisons Furthermore, only Caucasian boys were examined. In conclusion, our study suggests that longer AR (CAG)n are associated with increased prepubertal fat accumulation and shorter AR (CAG)n are associated with less pubertal fat accumulation. Furthermore, nonlinear associations between CAG length and both LH and testosterone were found in early puberty. Thus, this genetic variation appears to be important for metabolic and reproductive factors in healthy boys. 5. vis-Dao CA, Tuazon ED, Sokol RZ, Cortessis VK. Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis. J Clin Endocrinol Metab. 2007;92:4319 – 4326. 6. Rajpert-De Meyts E, Leffers H, Petersen JH, et al. CAG repeat length in androgen-receptor gene and reproductive variables in fertile and infertile men. Lancet. 2002;359:44 – 46. 7. Nenonen HA, Giwercman A, Hallengren E, Giwercman YL. Nonlinear association between androgen receptor CAG repeat length and risk of male subfertility—a meta-analysis. Int J Androl. 2011; 34:327–332. 8. Nenonen H, Bjork C, Skjaerpe PA, et al. CAG repeat number is not inversely associated with androgen receptor activity in vitro. Mol Hum Reprod. 2010;16:153–157. 9. Lappalainen S, Utriainen P, Kuulasmaa T, Voutilainen R, Jaaskelainen J. Androgen receptor gene CAG repeat polymorphism and X-chromosome inactivation in children with premature adrenarche. J Clin Endocrinol Metab. 2008;93:1304 –1309. 10. Voorhoeve PG, van Mechelen W, Uitterlinden AG, Delemarre-van de Waal HA, Lamberts SW. Androgen receptor gene CAG repeat polymorphism in longitudinal height and body composition in children and adolescents. Clin Endocrinol (Oxf). 2011;74:732–735. 11. Aksglaede L, Sorensen K, Petersen JH, Skakkebaek NE, Juul A. Recent decline in age at breast development: the Copenhagen Puberty Study. Pediatrics. 2009;123:e932– e939. 12. Sorensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal timing in healthy Danish boys: associations with body mass index. J Clin Endocrinol Metab. 2010;95:263–270. 13. Mouritsen A, Aksglaede L, Sorensen K, et al. The pubertal transition in 179 healthy Danish children: associations between pubarche, adrenarche, gonadarche and body composition. Eur J Endocrinol 2012;168:129 –136. 14. Aksglaede L, Sorensen K, Boas M, et al. Changes in anti-Mu¨llerian hormone (AMH) throughout the life span: a population-based study of 1027 healthy males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab. 2010;95:5357–5364. 15. Travison TG, Shackelton R, Araujo AB, et al. Frailty, serum androgens, and the CAG repeat polymorphism: results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2010;95: 2746 –2754. 16. Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia. 2003;46:31–39. 17. Nielsen TL, Hagen C, Wraae K, et al. The impact of the CAG repeat polymorphism of the androgen receptor gene on muscle and adipose tissues in 20⫺29-year-old Danish men: Odense Androgen Study. Eur J Endocrinol. 2010;162:795– 804. 18. Walsh S, Zmuda JM, Cauley JA, et al. Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men. J Appl Physiol. 2005;98:132–137. 19. McInnes KJ, Smith LB, Hunger NI, Saunders PT, Andrew R, Walker BR. Deletion of the androgen receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis. Diabetes. 2012;61: 1072–1081. 20. Sorensen K, Aksglaede L, Munch-Andersen T, et al. Sex hormonebinding globulin levels predict insulin sensitivity, disposition index and cardiovascular risk during puberty. Diabetes Care. 2009;32: 909 –914. or da p Address all correspondence and requests for reprints to: Annette Mouritsen, University Department of Growth and Reproduction, Rigshospitalet, Section 5064. E-mail: [email protected]. CD R Acknowledgments Co pi aa ut or iza This study was supported by the Sawmill Owner Jeppe Juhl and wife Ovita Juhls Memorial Fund, Aase and Einar Danielsen Foundation, Kirsten and Freddy Johansen Foundation, European Union FP7 (DEER; Grant Agreement 212844), and Danish Agency for Science, Technology and Innovation 09-067180 Danish Council for Strategic Research 2009 (DAN-ED; Grant Agreement 2107-05-0006). The study is registered in www.ClinicalTrials.gov Identifier: NCT01411527. Disclosure Summary: The authors have nothing to disclose. References 1. Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science. 1988;240:327–330. 2. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352:77–79. 3. 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; 22:3181–3186. 4. Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab. 1997;82:3777–3782. E609 25/04/2014 The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 24 April 2014. at 14:37 For personal use only. No other uses without permission. . All rights reserved.
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