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From * The Egyptian In Vitro Fertilization and
Embryo Transfer Centre, Hadayk El-Maadi, Cairo, Egypt;
Andrology Department, Faculty of Medicine,
Cairo University, Cairo, Egypt; Obstetrics
& Gynecology Unit, University of Wisconsin Medical School, Madison,
Wisconsin; and Bourn Hall Clinic, Cambridge,
United Kingdom.
| Correspondence to: Dr Marijo Kent-First, Department of Biological Sciences, Box GY, Mississippi State University, Mississippi State, MS 39672 (e-mail: mk247{at}msstate.edu). |
| Received for publication May 24, 2008; accepted for publication January 21, 2009. |
Androgens play key roles in spermatogenesis, and they exert their effect
via the androgen receptor (AR). The AR gene has a repetitive DNA sequence in
exon 1 that encodes a polyglutamine tract. Instability in the glutamine (CAG)
repeat unit length is polymorphic across ethnic groups. Previous studies of
the relationship between the repeat unit length and male infertility have been
contradictory. To establish the range of wild-type alleles in Egyptian men, we
determined the range of repeat lengths in a population of normally fertile,
ethnically selected Egyptian men. We also investigated the association between
trinucleotide repeat length within the AR gene and male factor
infertility in a population of ethnically selected Egyptian infertile men, who
were compared with fertile, ethnic group–matched and age-matched
controls. The study included 129 clinically selected infertile Egyptian men
who were scheduled for intracytoplasmic sperm injection and 52 ethnically
matched fertile controls. The experimental population was grouped according to
sperm counts ranging from nonobstructive azoospermia to normozoospermia. The
CAG repeat N-terminal domain region of the AR gene was amplified in
peripheral blood DNA, and allele size was determined by fragment analysis.
Allele size and single-nucleotide polymorphism and mutation rates were
determined by sequencing individual amplified alleles. The mean CAG repeat
length in the azoospermia group was 18.55 ± 2.0; in the severe
oligozoospermia group it was 18.21 ± 3.42; in the oligozoospermia group
it was 18.27 ± 2.93; and in the infertile with normal sperm count group
it was 17.72 ± 2.0. In the control group, the mean CAG repeat length
was 18.18 ± 3.63. No significant correlation was found between CAG
repeat length and the risk of male factor infertility in an ethnically defined
population of Egyptian men. However, a significant and positive correlation
between CAG repeat length and serum testosterone concentration was
demonstrated. This suggests the involvement of epigenetic regulation linked to
this region.
Key words: Male infertility, spermatogenesis, trinucleotide repeat
The AR gene is a single-copy gene located in the pericentric region of the long arm of the X chromosome, at locus Xq11-12 in the human (Brown et al, 1989). The AR gene contains 8 exons. Toward the 5' end of exon 1 there is a polymorphic glutamine (CAG) repeat that encodes a polyglutamine tract. This microsatellite locus is the most variable region in the AR gene. In a healthy individual, the number of CAG repeats ranges from 9 to 36, with an average of 21–22 repeats. The average number of repeat lengths varies significantly between different racial groups (Quigley et al, 1995). For example, individuals of African descent have much shorter average repeat lengths of CAG (18–20) compared with Hispanics (CAG, 23). Studies of CAG repeat lengths in whites and East Asians have reported the repeat lengths to be 21–22 and 23, respectively. Moreover, there are about 20 different allele lengths reported across ethnic groups, and 90% of women are heterozygous for the length of the repeat (Sartor et al, 1999; Bennett et al, 2002).
Spinal and bulbar muscular atrophy (SBMA; Online Mendelian Inheritance in Man no. 313200), also known as Kennedy disease, is linked to an abnormal elongation of more than 40 CAG repeats in exon 1 of the AR gene (Quigley et al, 1995). SBMA is a neurodegenerative disease characterized by progressive weakness and atrophy of proximal muscles. Most affected men display progressive androgen insensitivity in the form of progressive testicular atrophy, gynecomastia, feminized skin changes, and reduced fertility, which are either due to azoospermia or severe oligozoospermia (Greenland and Zajac, 2004).
Many studies have examined the possible correlation between the length of the polyglutamine repeat in the AR gene and male factor infertility (Table 1). A number of these reports suggested a link between male factor infertility and expansion of the polymorphic trinucleotide (CAG) repeat in the AR gene (Mifsud et al, 2001; Patrizio et al, 2001; Madgar et al, 2002). Other reports failed to demonstrate such an association (Giwercman et al, 1998; Dadze et al, 2000; Tufan et al, 2005). The basis for these investigations is the finding that the length of the polyglutamine repeat is inversely proportional to the degree of normal functionality of the AR (Kazemi-Esfarjani et al, 1995). This observation led to the hypothesis that significantly longer or significantly contracted polyglutamine tracts should be considered as a risk factor for male infertility. To test this hypothesis in any population, it is critical that the range of alleles present in ethnically matched (relative to the experimental population) fertile control men be determined (Zitzmann and Nieschlag, 2003). Unfortunately, data interpretations in many studies are confusing because of the general inherent instability of microsatellite loci and the specific selective instability of loci containing trinucleotide CAG repeats. Furthermore, given fluid migration patterns in human populations, the wide variation in repeat lengths within an ethnically mixed population(s) and the overlapping ranges between defined ethnic groups make it difficult to assess data interpretation and comparisons of data between ethnic groups (Hiort and Holterhus, 2003).
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The present study was designed to test the hypothesis that significant deviation from the mean CAG repeat length in the AR gene is correlated with male factor infertility. To test this hypothesis, first the relative stability (including the range of allele sizes) of the AR-CAG repeat length in an ethnically defined and population of fertile Egyptian men with normal semen parameters was determined. Second, the relationship of the AR-CAG repeat length relative to male factor infertility in an ethnically defined population of Egyptian men who were intracytoplasmic sperm injection (ICSI) candidates was determined. An ethnically selected wild-type population of fertile Egyptian men served as the control group in this study.
Materials and Methods
Subjects
A total of 129 infertile men presenting consecutively who were scheduled
for the ICSI program at the Egyptian In Vitro Fertilization and Embryo
Transfer Centre were prospectively recruited for the study during the period
from 2004 through 2005. Patients with obstructive azoospermia,
hypogonadotrophic hypogonadism, genital tract infection, and genetic or
karyotype abnormalities were excluded from the study. Infertile couples with
definite female factor infertility were also excluded. The control subjects
were fertile volunteers and patients attending urology clinics for complaints
other than infertility. Fifty-two men were recruited, all with proven
fertility, having fathered at least one child by natural conception. These men
had no previous history of infertility or fertility treatment and had no
identified genetic disorders. All cases and controls were identified as
Egyptians according to self-categorization. The geographic regions of descent
for all subjects in the control and experimental populations were derived from
the Nile Delta and Upper Egypt, both along the Nile River.
This study was conducted with institutional review board approval in The Egyptian In Vitro Fertilization and Embryo Transfer Centre and in the United States (Promega, Madison, Wisconsin). Each participant (patients and controls) gave written informed consent. The samples were made anonymous throughout the study.
Clinical Evaluation
Each patient was subjected to history taking and clinical examination.
Determination of testicular volume was performed by Orchidometer (Holtain Ltd,
Crymych, United Kingdom). Laboratory investigations included: semen analysis
according to World Health Organization
(1999) guidelines, measurement
of serum levels of reproductive hormones (follicle-stimulating hormone [FSH],
luteinizing hormone [LH], testosterone, and prolactin), and cytogenetic
analysis. The patient population was restricted according to the status of the
female partner's age (younger than 40 years), normal basal FSH level, no
polycystic ovary syndrome, and normal uterus with no hydrosalpinges detected
by ultrasonography. For each of the control subjects, at least one semen
analysis was performed, as well as clinical examination. For each participant
in the experimental and control groups, a peripheral blood sample was
collected for DNA analysis of sequence of CAG repeat length within the
AR gene. None of the patients received infertility treatment during
the 3 months prior to these investigations
Molecular Analysis
Allele Sizing and Trinucleotide Repeat Allele Fragment Analysis—
DNA was purified from the peripheral blood of patients and control subjects
using a Wizard Genomic DNA Purification System (Promega) and DNA IQ (Promega)
according to the manufacturer's recommended protocol. The CAG repeat within
the N-terminal domain region was amplified using 2 flanking sets of primers:
A(F) 5'-TCC AGA ATC TGT TCC AGA GCG TGC-3' and A1(R) 5'-GCT
GTG AAG GTT GCT GTT CCT CAT-3'. In set 1, the forward primer, A(F), was
fluorescently labeled and paired with the unlabeled high-performance liquid
chromatography (HPLC)–purified reverse primer, A1(R). In set 2, the
unlabeled HPLC–purified forward primer was paired with a fluorescently
labeled reverse A1(R) primer. A total of 120 ng of DNA was amplified in
duplicate experiments designed to establish and to confirm allele size. The
PCR-amplified products were also sequenced as needed to confirm CAG repeat
length and polymorphism. Conditions for large-pool PCR were as follows:
primers were diluted to 500 µM in a 40-µL total reaction volume
consisting of 4 µL of STAR buffer (Promega) and AmpliTaq Gold DNA
polymerase (0.5 µL/reaction; Applied Biosystems, Foster City, California)
PCR was performed using the ABI GeneAmp PCR system 9600 (Perkin Elmer,
Norwalk, Connecticut) according to the Hot Start cycle protocol. The Hot Start
cycle was 95°C for 9 minutes, followed by 95° denaturation for 1
minute, 60° annealing for 1 minute, and 72° extension for 1 minute for
40 cycles, followed by a final extension at 72° for 5 minutes. The
products were separated by capillary electrophoresis on ABI PRISM 3100 Genetic
Analyzers with allele sizing using ILS-600TM, 60–600 bp (Promega). PCR
controls used in amplification experiments included water, male DNA, and
female DNA.
Fragment Size Confirmation and SNP Genotyping— PCR products from a total of 75 individuals (40 samples from the experimental group and 35 samples from the control group) were gel purified according to standard methods. Both the forward and reverse strands were sequenced to confirm the length of the CAG repeat and to identify SNPs within the region immediately flanking the CAG repeat.
Statistical Analysis
Statistical analysis was performed using the statistical package SPSS for
Windows (version 11.0; SPSS Inc, Chicago, Illinois). The difference in the CAG
repeat length between control, combined infertile group, and various subgroups
of infertile men was evaluated by the Mann-Whitney U test. Spearman's
correlation coefficient was used for bivariate regression analysis to
determine the correlation between CAG repeat length, sperm count, bitesticular
volume, and hormone data. A probability of P < .05 was considered
statistically significant.
Results
Clinical Findings
This study included 129 infertile, ethnically restricted patients scheduled
for an ICSI program. The group included 44 patients with nonobstructive
azoospermia (absence of sperm in the ejaculate confirmed by examination of
sediment after centrifugation), 43 patients with severe oligozoospermia (sperm
count <5 million/mL), 31 patients with oligozoospermia (sperm count range
from 5 million/mL to less than 20 million/mL), and 11 patients with normal
sperm counts and varying degrees of asthenozoospermia/teratozoospermia (sperm
count 
20 million/mL). A summary of the clinical and molecular data is
shown in Table 2. The control
group consisted of 52 fertile men with fertility demonstrated by live births
and sperm counts ranging from 20 million/mL to 100 million/mL (mean, 53.19
± 17.83 million/mL). The ethnically selected control population was
matched with the experimental population according to both ethnicity and age.
In the combined infertile group, excluding infertile patients with normal
sperm counts, the sperm concentrations ranged between 0 and 19 million/mL
(mean, 3.37 ± 5.25 million/mL; Table
3). Bitesticular volume in the infertile group ranged between 2
and 66 mL (mean, 28.97 ± 14.3 mL), whereas in the control group the
range was between 34 and 70 mL (mean, 49 ± 9.29 mL), which was
significantly different (P < .05). The sperm count was
significantly correlated with bitesticular volume (P = .01) and serum
levels of FSH (P = .001), LH (P = .001), and testosterone
(P = .04).
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High serum FSH was detected in 40 patients from the experimental population, and an isolated high serum FSH was detected in 18 infertile patients. High serum LH was detected in 28 patients. Combined high serum LH and serum testosterone were detected in only 3 patients. These 3 patients had sperm counts of 0 (azoospermia), 0.5 million/mL, and 6 million/mL, respectively, and the lengths of their mean CAG repeats were 19, 19, and 21, respectively. A total of 38 patients (29.5%) had undergone bilateral or left varicocelectomy. A total of 10 patients (7.8%) had an undescended testis. One patient had a nonmalignant testicular tumor with subsequent left orchidectomy. Parents' consanguinity was reported by 26 patients (20.2%), whereas another 9 patients (7%) had a history of infertility in first- or second-degree relatives.
Molecular Findings: Length of AR-CAG Repeats
The means and ranges of CAG repeat lengths in control and different
infertile groups are summarized in Table
2. The mean CAG repeat length did not differ statistically between
the combined infertile group (18.30 ± 2.3) and the control group (18.18
± 3.63). When infertile men with normal sperm count were excluded, the
mean CAG repeat length of the remaining group (18.35 ± 3.02) did not
differ significantly from that of the control group
(Table 3). The mean CAG repeat
length did not differ statistically between the control group and each of the
infertile subgroups in the experimental population.
A total of 40 patients with azoospermia were subjected to testicular sperm extraction (TESE) as a part of their ICSI schedule (another 4 patients were scheduled for ICSI/TESE and dropped out before the procedure). Sperm retrieval was successful in 34 patients. The mean length of CAG repeat did not reveal a significant difference between azoospermic patients with positive sperm retrieval and those with negative sperm retrieval (Table 3).
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None of the semen parameters or the other hormone parameters was significantly correlated with length of CAG repeat. On the other hand, there was no correlation between length of CAG repeat and bitesticular volume or sperm count in the fertile control group.
The distribution of CAG repeat lengths in the control group and experimental infertile group is shown in the Figure. The CAG repeat lengths in the control, total infertile group, and infertile subgroups overlap considerably. The longest allele (26 repeats) was detected in 3 individuals: 1 person from the control group, 1 patient with azoospermia, and 1 patient with severe oligozoospermia. The shortest allele (6 repeats) was detected in 1 patient with severe oligozoospermia.
In the combined infertile group, the most common alleles were 17 and 19 repeats. Each of these respective alleles was detected in 20 patients (15.5%). In the control group, the most common allele (18 repeats) was detected in 9 individuals (17.3%). No sequence variation or polymorphism was observed in alleles isolated from 75 individuals.
Sequence analysis of PCR products confirmed repeat length in all of the sampled alleles.
Discussion
The present study examines the association between expanded CAG repeat length within the AR gene and defective spermatogenesis in 129 infertile and 52 control men of matched Egyptian origin. The first experiment established the common alleles present in an ethnically restricted population of normally fertile men. This population then served as the control for the clinically selected experimental population. There was no correlation between CAG repeat length and defective spermatogenesis. The mean numbers of repeats in the infertile population and fertile controls were similar (18.30 ± 2.30 and 18.18 ± 3.63, respectively).
The current study is the first to examine this correlation in a defined Egyptian population, and this adds to the data available for different ethnic backgrounds. The mean CAG repeat length for the combined control and infertile groups was 18.24 ± 2.96, with a range of 6–26 repeats. Although several studies have investigated the proposed association, these reports have yielded conflicting results (Table 1). The observed variations in the results from previous studies stem from several factors: 1) ethnically diverse populations; 2) the studied infertile men may represent a heterogeneous group with respect to the causes of infertility and may be under the effect of different genetic mutations or even epigenetic phenomena; and 3) different inclusion criteria in each study. The previously studied infertile populations included various categories of infertility (eg, patients with varicocele, genital tract obstruction, and/or genital tract infection) and semen parameters (azoospermia, oligozoospermia, severe oligozoospermia, or infertile men with normal sperm count associated with varying degrees of asthenozoospermia/teratozoospermia; Kukuvitis et al, 2002; Asatiani et al, 2003; Hadjkacem et al, 2004). Most importantly, the control groups in many of these previous studies were not well matched in terms of ethnicity and age. The control groups in these studies often included not only individuals with proven fertility, but also individuals with normal sperm count but not proven fertility and/or individuals from unselected populations (Legius et al, 1999; Erasmuson et al, 2003; Lund et al, 2003).
Unfortunately, these different reports render the comparison between various studies inconclusive. Because of racial variation and the impact of ethnicity, it is possible that the results for AR-CAG repeat length in selectively restricted racial/ethnic populations outweigh those for a mixed population (Asatiani et al, 2003).
Some biomedical scientists assume that racial/ethnic categorizations are inadequate descriptors of the distribution of genetic variation in humans (Schwartz, 2001; Hega and Venter, 2003). However, studies of different populations have documented genetic, and therefore, biological differences among races (Keita et al, 2004). Genetic variation tends to be geographically structured in accordance with the classic common racial classification, which is based on continental ancestry: African, white, Asian, Pacific Islander, and Native American (Jorde and Wooding, 2004; Tishkoff and Kidd, 2004). It could be argued that population clusters identified by genotype analysis seem to be more informative than those identified by self-declaration of race (Wilson et al, 2001). However, Risch et al (2002) demonstrated that from both an objective and scientific (genetic and epidemiologic) perspective, there is great validity in racial/ethnic self-categorizations.
The present work studied only an ethnically defined population; all subjects were Egyptian by self-declaration. Egypt's geographic location has prompted its population's genetic diversity, but despite this, the Egyptian population seems to be fairly homogenous. This is supported by the findings of genetic studies that characterize the Egyptian population. Studies of mitochondrial DNA variation, the Y-chromosome gene pool, and different allelic variants in the modern Egyptian reflect a mixture of European, Middle Eastern, and African characteristics (Manni et al, 2002; Hamdy et al, 2003). In addition, there is still a homogenous genetic tie to ancient Egyptians (Kring et al, 1999). On the other hand, these studies distinguished genetic characteristics of the Egyptian from those of sub-Saharan populations (Luis et al, 2004). This supports the concept that human populations are seldom demarcated by precise genetic boundaries, and substantial overlap can occur (Risch et al, 2002). The Egyptian population, although fairly homogenous, is no exception in this regard.
A recent comprehensive meta-analysis included a summary of 33 reports. This study investigated the source of CAG variation between published results (Davis-Dao et al, 2007). The report indicated that case and control definitions likely influenced study results as an important determinant of differences in repeat length between cases and controls. In the present work, in accordance with the recommendation of that meta-analysis, we considered stringency of case and control definitions. On the other hand, the analysis of the full set of 33 reports revealed statistically significant longer CAG repeat length among cases compared with control populations. In an attempt to avoid methodologic concerns, particularly small sample size and unmatched case-control, Westerveld et al (2008) investigated AR-CAG repeat in 700 men who presented for fertility workup with varying degrees of semen quality. The study concluded that there was no correlation between CAG repeat length expansion in the AR gene and semen quality. However, the study included an experimental population of men from mixed ethnic origins with no matched control population. Exon 1 of the AR gene contains another island of polymorphic microsatellite GGC repeats. It was proposed that certain combinations of CAG and GGC repeats may confer a risk of infertility to the carriers. However, previous studies showed that there was no association between AR CAG/GGN microsatellites and impaired spermatogenesis (Ruhayel et al, 2004; Rajender et al, 2006; Saare et al, 2007).
In the present study, there was a mild positive correlation between CAG repeat length and the level of serum testosterone in 3 of the subgroups of the infertile patients studied (combined infertile, infertile excluding patients with normal sperm count, and patients with normal sperm count; but not in azoospermia, severe oligospermia, or oligspermia groups). Although some studies found no significant association between AR-CAG and hormonal levels, particularly testosterone (Alevizaki et al, 2003; Harkonen et al, 2003), one study reported strikingly higher level of LH and androgen sensitivity index (ASI) in azoospermic patients with short CAG repeats (Tse et al, 2003). Other reports are in agreement with our findings and show a positive correlation between AR-CAG repeats and serum levels of LH, free testosterone, and ASI (Giwercman et al, 2004). This hormone profile is often reported in men with a range of clinical phenotypes associated with aberrant secondary sex characteristics. Lim et al (2000) reported longer AR-CAG repeats to be associated with moderate to severe undermasculinized genitalia in XY men. In addition, Canale et al (2005) investigated CAG repeat length in 3 groups: control, infertile, and hypoandrogenized subjects. They concluded that hypoandrogenic traits, such as hypoplasia of the prostate and seminal vesicles, and reduced beard and body hair, are associated with longer CAG repeats. However, they found no difference in the mean of CAG repeats in infertile populations compared with fertile control populations.
In the present work, the secondary sexual characteristics of infertile groups were comparable to those of controls. Because there was no difference between the CAG repeat length in the 2 different groups (infertile vs control), the proposed effect of CAG repeat length on testosterone functionality may be limited to a subclinical level.
Thus, it might be assumed, at least in our studied population, that the AR modulates its transactivation potential via its N-terminal polyglutamine tract without being associated with any pathologically apparent disease (pathologic phenotype; Vogt, 1999).
In conclusion, our study established the range of alleles in an ethnically and geographically restricted population of Egyptian men with normal fertility. There was no significant correlation between CAG repeat length and risk of male infertility in our ethnically restricted experimental population compared with the matched control population. Therefore, polymorphism detected in the polyglutamine-rich region of the AR gene is not a useful genetic indication of male factor infertility. A significant positive correlation between CAG repeat length and serum testosterone concentration was detected, and this suggests that epigenetic regulation linked to this region is involved.
References
Alevizaki M, Cimponeriu AT, Garofallaki M, Sarika HL, Alevizaki CC, Papamichel C, Philippou G, Anastasiou EA, Lekakis JP, Mavrikakis M. The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol. 2003; 59: 749 –755.[CrossRef][Medline]
Asatiani K, Von Eckardstein S, Simoni M, Gromoli J, Nieschlag E. CAG repeat length in the androgen receptor gene affects the risk of male infetility. Int J Androl. 2003; 26: 255 –261.[CrossRef][Medline]
Bennett CI, Price DK, Kim S, Liu D, Jovanovice BD, Nathan D,
Johnson ME, Montgomery JS, Cude K, Brockbank JC, Sartor O, Figg WD. Racial
variation in CAG repeat length within the androgen receptor gene among
prostate cancer patients of lower socioecomomic status. J Clin
Oncol. 2002;20: 3599
–3604.
Brown CJ, Goss SJ, Lubahn DB, Joseph DR, Wilson EM, French FS, Willard HF. Androgen receptor locus on the human X-chromosome: regional localization to Xp11-12 and description of a DNA polymorphism. Am J Hum Genet. 1989;44: 264 –269.[Medline]
Canale D, Caglieresi C, Moschini C, Liberati CD, Macchia E, Pinchera A, Martino E. Androgen receptor polymorphism (CAG repeats) and androgenicity. Clin Endocrinol. 2005; 63: 356 –361.[CrossRef][Medline]
Dadze S, Wieland C, Jakubiczka S, Funke K, Schroder E, Royer-Pokora
B, Willers R, Wieacker P. The size of the CAG repeat in exon 1 of the androgen
receptor gene shows no significant relationship to impaired spermatogenesis in
an infertile Caucasian sample of German origin. Mol Hum
Reprod. 2000;6: 207
–214.
Davis-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 Endocrin Metab. 2007; 92(11): 4319
–4326.
Dhillon VS, Husain SA. Cytogentic and molecular analysis of the Y chromosome: absence of a significant relationship between CAG repeat length in exon 1 of the androgen receptor gene and infertility in Indian men. Int J Androl. 2003; 26: 286 –295.[CrossRef][Medline]
Dowsing AT, Yong EL, Clark M, Mclachlan RI, de Kretser DM, Trounson A. Linkage between male infertility and trinucleotids repeat expansion in the androgen receptor gene. Lancet. 1999; 354: 640 –643.[CrossRef][Medline]
Erasmuson T, Sin IL, Sin YT. Absence of association of androgen receptor trinucleotide expansion and poor semen quality. Int J Androl. 2003;26: 46 –51.[CrossRef][Medline]
Giwercman Y, Richthoff J, Lilja H, Anderberg C, Abrahamsson P, Giwercman A. Androgen receptor CAG repeat length correlates with semen PSA level in adolesence. Prostate. 2004; 59: 227 –233.[CrossRef][Medline]
Giwercman YL, Xu C, Arver S, Pousette A, Reneland R. No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men. Clin Genet. 1998; 54: 435 –436.[Medline]
Gobinet J, Poujol N, Sultan C. Molecular action of androgens. Mol Cell Endocrinol. 2002; 198: 15 –24.[CrossRef][Medline]
Gottlieb B. The androgen receptor gene mutation database. Montreal, QC, Canada: McGill University; April 4, 2005. http://www.mcgill.ca/androgendb. Accessed April 27, 2008.
Gottlieb B, Lombroso R, Beitel LK, Trifiro MA. Molecular pathology of the androgen receptor in male (in)fertility. Reprod Biomed Online. 2005;10: 42 –48.[Medline]
Greenland KJ, Zajac JD. Kennedy's disease: pathogenesis and clinical approaches. Intern Med J. 2004; 34: 279 –286.[CrossRef][Medline]
Hadjkacem L, Hadj-Kacem H, Boulila A, Bahloul A, Ayadi H, Ammar-Keskes L. Androgen receptor gene CAG repeats length in fertile and infertile Tunisian men. Ann Genet. 2004; 47: 217 –224.[Medline]
Hamdy S, Hiratsuka M, Narahara K, Endo N, El-Enany M, Moursi N, Ahmed M, Mizugaki M. Gentotype and allele frequencies of TPMT, NAT2, GST, SULTIAI and MDR-I in the Egyptian population. Br J Clin Pharmacol. 2003; 55(6): 560 –569.[CrossRef][Medline]
Harkonen K, Hhtaniemi I, Makinen J, Hubler D, Irjala K, Koskenvo M, Oettel M, Raitakari O, Saad F, Pollanen P. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptomes in ageing men. Int J Androl. 2003; 26: 187 –194.[CrossRef][Medline]
Hega SB, Venter JC. Genetics. FDA races in wrong direction.
Science. 2003;301: 466
.
Hiort O, Holterhus PM. Androgen insensitivity and male infertility. Int J Androl. 2003; 26: 16 –20.[CrossRef][Medline]
Jorde LB, Wooding SP. Genetic variation, classification and race. Nat Genet. 2004; 36: S28 –S33.[CrossRef][Medline]
Katagiri Y, Neri QV, Takeuchi T, Moy F, Sills ES, Palermo GD. Androgen receptor CAG polymorphism (Xq11-12) status and human spermatogenesis: a prospective analysis of infertile males and their offspring conceived by intracytoplasmic sperm injection. Int J Mol Med. 2006; 18(3): 405 –413.[Medline]
Kazemi-Esfarjani P, Trifiro MA, Pinsky L. Evidence for a repressive
function of the long polyglutamine tract in the human androgen receptor:
possible pathogenetic relevance for the (CAG)n-expanded neuronopathies.
Hum Mol Genet. 1995; 4: 523
–537.
Keita SOY, Kitles RA, Royal CD, Bonney GE, Furbert-Harris P, Dunston GM, Rotimi CN. Conceptualizing human variation. Nat Genet. 2004;36: S17 –S20.[CrossRef][Medline]
Komori S, Kasumi H, Kanazawa R, Sakata K, Nakata Y, Kato H, Kovama
K. CAG repeat length in the androgen receptor gene of infertile Japanese males
with oligozoospermia. Mol Hum Reprod. 1999; 5: 14
–16.
Kring M, Salem A, Bauer K, Geisert H, Malek A, Chaix L, Simon C, Welsby D, Di-Rienzo A, Utermann G. mtDNA analysis of Nile River valley population: a genetic corridor or a barrier to migration? Am J Hum Genet. 1999;64: 1166 –1176.[CrossRef][Medline]
Kukuvitis M, Gerorgiou I, Bouba I, Tsirka A, Ciannouli C, Yapijakis C, Traiatzis B, Bontis J, Lolis D, Sofikitis N, Papadimas J. Association of oestrogen receptor polymorphisms and androgen receptor CAG trinucleotide repeats with male infertility: a study in 109 Greek infertile men. Int J Androl. 2002; 25: 149 –152.[CrossRef][Medline]
Lavery R, Houghton JA, Nolan A, Glennon M, Egan D, Maher M. CAG repeat length in an infertile male population of Irish origin. Genetica. 2005; 123: 295 –302.[CrossRef][Medline]
Legius E, Vanderschueren D, Spiessens C, D'Hooghe T, Matthijs G. Association between CAG repeat number in the androgen receptor and male infertility in a Belgian study. Clin Genet. 1999; 56: 166 –167.[CrossRef][Medline]
Lim H, Chen H, McBride S, Dunning A, Nixon R, Hughes I, Hawkins J.
Longer polyglutamine tracts in the androgen receptor are associated with
moderate to severe undermasculinized genitalia in XY males. Hum Mol
Genet. 2000;9: 829
–834.
Luis J, Rowold D, Regueiro M, Caeiro B, Cinnioglu C, Roseman C, Underhill P, Cavalli-Sforza L, Herrera R. The Levant versus the Horn of Africa: evidence for biderictional corridor of human migration. Am J Hum Genet. 2004;74: 532 –544.[CrossRef][Medline]
Lund A, Tapanainen JS, Lahdetie J, Savontaus M, Attomaki K. Long CAG repeats in the AR gene are not associated with infertility in Finnish males. Acta Obstet Gynecol Scand. 2003; 82: 162 –166.[CrossRef][Medline]
Madgar I, Green L, Kent-First M, Weissenberg R, Gershoni-Baruch R, Goldman B, Friedman E. Genotyping of Israeli infertile men with idiopathic oligozoospermia. Clin Genet. 2002; 62: 203 –207.[CrossRef][Medline]
Manni F, Leonardi P, Barakat A, Rouba H, Heyer E, Klintschar M, Mcelreavey K, Quintana-Murci L. Y-chromosome analysis in Egypt suggests a genetic regional continuity in Northeastern Africa. Hum Biol. 2002;74: 645 –658.[Medline]
Mengual L, Oriola J, Ascaso C, Oliva R. An increase CAG repeat
length in the androgen receptor gene in azoospermic ICSI candidates.
J Androl. 2003;24: 279
–284.
Mifsud A, Sim KS, Boettger-Tong H, Moreira S, Lamb DJ, Lipshultz I, Yong EL. Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of risk for male infertility. Fertil Steril. 2001;75: 275 –281.[CrossRef][Medline]
Molenda H, Kilts C, Allen R, Tetel M. Nuclear receptor coactivator
funuction in reproductive physiology and behavior. Biol
Reprod. 2003;69: 1449
–1457.
Nakabayashi A, Sueoka K, Matsuda N, Asada H, Tanigaki R, Sato K, Tajima H, Ogata T, Kuji N, Yoshimura Y. Incidental deviation of short and long CAG repeats in the androgen receptor gene for Japanese male inferility. Reprod Med Biol. 2003; 2: 145 –150.[CrossRef]
Pan H, Li YY, Li TC, Tsai WT, Li SY, Hsiao KM. Increased (CTG/CAG)n
lengths in myotonic dystrophy type 1 and Machado-Joseph disease genes in
idiopathic azoospermia patients. Hum Reprod. 2002; 17: 1578
–1583.
Patrizio P, Leonard DB, Chen K, Hernandez-Ayup S, Trounson A. Larger trinucleotide repeat size in the androgen receptor gene of infertile men with extremely severe oligozoospermia. J Androl. 2001; 22: 444 –448.[Abstract]
Quigley CA, De Bellis A, Marscheke KB, El-Awady MK, Wilson EM,
French FS. Androgen receptor defects: historical, clinical, and molecular
perspectives. Endocr Rev. 1995; 16: 271
–317.
Rajender S, Rajani V, Gupta N, Chakravarty B, Singh L, Thangaraj K.
No association of androgen receptor GGN repeat length polymorphism with
infertility in Indian men. J Androl. 2006; 27: 785
–789.
Rajpert-De Meyts ER, Leffers H, Petersen JH, Anderson AG, Carlsen E, Jorgensen N, Skakkebaek NE. CAG repeat length in androgen receptor gene and reproductive variables in fertile and infertile men. Lancet. 2002;359: 44 –46.[CrossRef][Medline]
Risch N, Burchard E, Ziv E, Tang H. Categorization of humans in biomedical research: genes, race and disease. Genome Biol. 2002;3: 1 –12.
Ruhayel Y, Lundin KB, Giwercman Y, Hallden C, Willen M, Giwercman
A. Androgen receptor gene GGN and CAG polymorphisms among severely
oligozoospermic and azoospermic Swedish men. Hum
Reprod. 2004;19: 2076
–2083.
Saare M, Belousova A, Punab M, Peters M, Haller K, Ausmees K, Poolamets O, Karro H, Metspalu A, Salumets A. Androgen receptor gene haplotype is associated with male infertility. Int J Androl. 2007; 31: 395 –402.[CrossRef]
Sartor O, Zheng Q, Eastham JA. Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology. 1999;53: 378 –380.[CrossRef][Medline]
Sasagawa I, Suzuki Y, Ashida J, Nakada T, Muroya K, Ogata T. CAG repeat length analysis and mutation screening of the androgen receptor gene in japanese man with idiopathic azoospermia. J Androl. 2001; 22: 804 –808.[Abstract]
Schwartz RS. Racial profiling in medical research. N Engl J Med. 2001;344: 1392 –1393.[CrossRef][Medline]
Thangaraj K, Joshi MB, Reddy AG, Gupta NJ, Chakravarty B, Singh L.
CAG repeat expansion in the androgen receptor gene is not associated with male
infertility in Indian populations. J Androl. 2002; 23: 815
–818.
Tishkoff SA, Kidd KK. Implications of biogeography of human populations for `race' and medicine. Nat Genet. 2004; 36: 521 –527.
Tse JYM, Liu VWS, Yeung WSB, Lau EYL, Ng EHY, Ho PC. Molecular analysis of the androgen receptor gene in Hong Kong Chinese infertile men. J Assist Reprod Genet. 2003; 20: 227 –233.[CrossRef][Medline]
Tufan A, Stiroglu-Tufan NL, Aydinuraz B, Stiroglu MH, Aydos K, Bagci H. No association of the CAG repeat length in exon 1 of the androgen receptor gene with idiopathic infertility in Turkish men: implications and literature review. Tohoku J Exp Med. 2005; 206: 105 –115.[CrossRef][Medline]
Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL. Long
polyglutamine tracts in the androgen receptor are assoicated with reduced
trans activation, impaired sperm production, and male infertility.
J Clin Endocrinol Metab. 1997; 82: 3777
–3782.
Van Golde R, Van Houwelingen K, Kiemeney L, Kremer J, Tuerlings J, Schalken J, Meuleman E. Is increased CAG repeat length in the androgen receptor gene a risk factor for male subfertility? J Urol. 2002;167: 621 –623.[CrossRef][Medline]
Verrijdt G, Tanner T, Moehren U, Gallewaert L, Haelens A, Claessens F. The androgen receptor DNA-binding domain determines androgen selectivity of transcriptional response. Biochem Soc Trans. 2006; 34: 1089 –1094.[CrossRef][Medline]
Vogt PH. Risk of neurodegenerative diseases in children conceived by intracytoplasmic sperm injection. Lancet. 1999; 354: 61 .
Von Eckardstein S, Syska A, Gromoll J, Kamischke A, Simoni M,
Nieschlag E. Inverse correlation between sperm concentration and number of
androgen receptor CAG repeats in normal men. J Clin Endocrinol
Metab. 2001;86: 2585
–2590.
Wallerand H, Remy-Martin A, Chabannes E, Bermont L, Adessi G, Bittard H. Relationship between expansion of the CAG Repeat in exon 1 of the androgne receptor gene and idiopathic male infertility. Fertil Steril. 2001;76: 769 –774.[CrossRef][Medline]
Westerveld H, Visser L, Tanck M, van deer Veen F. CAG repeat length variation in the androgen receptor gene is not associated with spermatogenic failure. Fertil Steril. 2008; 89: 253 –259.[CrossRef][Medline]
Wilson JF, Weale ME, Smith AC, Gratrix F, Fletcher B, Thomas MF, Bradman N, Goldstein DB. Population genetic structure of variable drug response. Nat Genet. 2001; 29: 265 –269.[CrossRef][Medline]
World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th ed. Cambridge, United Kingdom: Cambridge University Press; 1999 .
Yong EL, Loy CJ, Sim KS. Androgen receptor gene and male
infertility. Hum Reprod Update. 2003; 9: 1
–7.
Yoshida KI, Yano M, Chiba K, Honda M, Kitahara S. CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia. Urology. 1999; 54: 1078 –1081.[CrossRef][Medline]
Zitzmann M, Nieschlag E. The CAG repeat polymorphism within androgen receptor gene and maleness. Int J Androl. 2003; 26: 73 –83.
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