Male Infertility and Variation in CAG Repeat Length in the Androgen Receptor Gene: A Meta-analysis

Davis-Dao, Carol A.; Tuazon, Ellenie; Sokol, Rebecca Z.; Cortessis, Victoria K.

doi:10.1210/jc.2007-1110

Cited by 123 publications

(85 citation statements)

References 52 publications

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“…The above two studies [Davis-Dao et al 2007; has shown a direct correlation of AR CAG length with free testosterone in fertile men. Although not observed in all populations [Dadze et al 2000], depressed spermatogenesis has been associated with long CAG tracts in men from Singapore [Tut et al 1997], Australia [Dowsing et al 1999], Japan [Yoshida et al 1999], and the USA Patrizio et al 2001].…”

Section: Resultsmentioning

confidence: 73%

Effect of smoking on semen quality, FSH, testosterone level, and CAG repeat length in androgen receptor gene of infertile men in an Indian city

Mitra

Chakraborty

Mukhopadhay

et al. 2012

Systems Biology in Reproductive Medicine

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This study was conducted as part of an epidemiological survey of 126 nonsmokers and 178 smokers, showing primary infertility residing around Kolkata region of Eastern India. Their lifestyle history including smoking habits along with semen and blood were collected. The study examined the association of cigarette smoking with the risk of infertility, by determining the semen quality, follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone levels, and androgen receptor (AR)-CAG repeat length in a group of smokers compared with a control group (non smokers). Based on conventional WHO criteria, lower sperm motility (P < 0.001) and increased sperm morphological defects (P < 0.0001) were associated with smoking habits. Binary logistic regression analysis for the effect of smoking status on sperm DNA integrity demonstrated significant positive correlation (p = 0.006). Serum FSH and LH levels were higher for smokers compared with non-smokers while the testosterone level decreased significantly with the increasing smoking habit. The mean length of CAG repeats in AR gene was significantly higher for smokers with low testosterone compared to non-smokers. The study suggested that smoking is associated with altered semen quality, endocrine hormonal status, and number of CAG repeats in the AR gene.

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Section: Resultsmentioning

confidence: 73%

Effect of smoking on semen quality, FSH, testosterone level, and CAG repeat length in androgen receptor gene of infertile men in an Indian city

Mitra

Chakraborty

Mukhopadhay

et al. 2012

Systems Biology in Reproductive Medicine

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“…As a matter of fact, it is commonly accepted that the number of AR-CAG repeats coregulate the AR transactivation capacity in an inverse manner: the higher the number of AR-CAG repeats the lower the activity [17]. The identification of Kennedy syndrome (>40 CAG repeats with hypoandrogenism due to mild androgen insensitivity coupled with spinobulbar muscular atrophy), the results of two clinical observational studies [higher serum Tables 1 and 2 (free) T levels in those men with higher number of AR-CAG repeats] [15,16] and a recent meta-analysis (infertile men had <1 number of AR-CAG repeats than infertile men) [38] have supported that hypothesis. Conversely, both two recent "in vitro" papers [14,39] and a meta-analysis [23] have provided data that are in disagreement with the previous evidence showing a lack of a stepwise reduction in activity with a rise in AR-CAG length across the polymorphic range.…”

Section: Discussionmentioning

confidence: 99%

Could androgen receptor gene CAG tract polymorphism affect spermatogenesis in men with idiopathic infertility?

Giagulli

Carbone²,

Pergola

et al. 2014

J Assist Reprod Genet

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Purpose This study examined whether the AR-CAG repeat length might affect clinical characteristics (testis volume) seminal parameters (sperm count and its mobility) along with hormonal serum profile [FSH, LH, Testosterone (T) and Inhibin B (InhB)] both in idiopathic male infertility (IM) and in infertility due to a previous condition of cryptorchidism (CryM) or to Y chromosome long arm microdeletions (YM). Design Observational study without intervention(s).Patients One hundred and ten IM patients [90 idiopathic olizoospermic males (IOM) and 20 idiopathic azoospermic males (IAM)], 19 CryM male and 10 YM patients were included. Sixty-one age-matched healthy men who had fathered within 3 years were involved representing the control group (FM). Results AR-CAG repeats stretch was significantly longer in IOM (p<0.05), CryM (p<0.05) and YM (p<0.001) than FM. When the AR-CAG repeat tracts were subdivided in three subgroups according to the length of CAG repeats tract assessed in fertile subjects (the one with the middle (n 19-21) belonging to the 25 and 75 % inter-quartile, the ends belonging to the <25 % interquartile and >75 % inter-quartile, respectively), there was a statistically significant difference of distribution of AR-CAG tract length among fertile and different groups of infertile men (p= <0.0005; chi-square test). Moreover, the subgroup of AR-CAG repeat stretch with 22-28 triplets was associated with lower levels of InhB both in idiopathic oligozoospermic (Scheffe, Bonferroni and Dunett tests p = < 0.01) and azoospermic men (Scheffe, Bonferroni and Dunett test p=<0.05), while, when FM and men with idiopathic infertility were gathered in a single group, both the subgroup of AR-CAG tract with 15-18 repeats and the one with 22-28 repeats are associated with lower testis volume, reduced sperm count and serum InhB levels. Conclusions Our study showed that the outliers of AR-CAG repeat length seem to influence the function of AR, affecting testis volume and Sertoli cell function and consequently sperm production in both fertile and idiopathic infertile men.Keywords CAG repeat length polymorphism . Idiopathic male infertility . Y chromosome long arm microdeletions . Sertoli cell . Leydig cell . Inhibin B and testosteroneCapsule No concrete evidence about the pathogenetic role of androgen receptor (AR) CAG repeat length polymorphism in infertile men has been obtained so far. This study aims to search it, measuring AR-CAG polymorphism both in fertile and in infertile men with idiopathic infertility or with well-known causes of infertility (i.e. cryptorchidism and Ychromosomal microdeletions). The shortest tract as well as the longest one of AR-CAG repeat polymorphism may negatively affect the spermatogenesis in fertile and infertile men.

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“…These include premature adrenarche and acne in females, and an increased risk of metastatic disease in prostate cancer (34,35). Conversely, longer CAG repeats have been associated with idiopathic hypospadias, undescended testes and decreased sperm counts (36)(37)(38). The association with cryptorchidism is stronger when combined analysis of CAG and GGC repeat lengths is performed (39).…”

Section: Inguinoscrotal Phasementioning

confidence: 99%

Factors controlling testis descent

Hughes¹,

Acerini²

2008

European Journal of Endocrinology

142

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Descent of the testis from an intra-abdominal site in foetal life to an extracorporeal location after birth is a mandatory developmental process to ensure that the mature testis promotes normal spermatogenesis. The two phases of transabdominal and inguinoscrotal descent occur approximately during the first and last thirds of gestation respectively. Key anatomical events to release the testis from its urogenital ridge location and to guide the free gonad into the scrotum are the degeneration of the cranio-suspensory ligament and a thickening of the gubernaculum. Androgens play a role in both these processes, particularly with respect to enabling the testis to traverse the inguinal canal in the final phase of descent. Experiments in animals suggest that androgens mediate this effect via the release of calcitonin gene-related peptide by the genitofemoral nerve, but direct evidence for such a mechanism is lacking in humans. The transabdominal phase of descent is under the control of insulinlike 3 (INSL3), a product of the Leydig cells. Definitive evidence of its role in rodent testis descent is illustrated by the phenotype of bilateral cryptorchidism in Insl3K/K null mice. Circulating levels of INSL3 are higher in boys at puberty, are undetectable in girls and are lower in boys with undescended testes. A minority also have a mutation either in the INSL3 gene or affecting its receptor gene, relaxin/insulin-like family peptide receptor 2 (LGRF8). Other factors that may play a role in testis descent include the anti-Mullerian hormone and members of the HOX gene family. Evidence that the prevalence of undescended testis may be increasing provides a phenotypic readout for the effects of postulated chemicals in the environment interfering in some way with the action of factors that control testis descent. Epidemiological studies point to profound geographical variations in prevalence in countries such as Denmark and Finland. Associations have been found with levels of chemicals labelled as endocrine disruptors being higher in breast milk samples from mothers with cryptorchid boys when compared with controls. The adverse effects of these compounds (e.g. bisphenol A) can be replicated in the offspring of dams exposed during pregnancy. A sensitive marker of an anti-androgen effect of a compound is a reduction in the anogenital distance, an anthropometric measurement that is significantly greater in males compared with females. The observation of an association between the anogenital distance in infant boys and the level of pesticides in the urine of their mothers in late gestation indicates that this has the potential to be a useful surrogate marker of the effects of environmental chemicals on testis descent in human population studies. The rightful place for the testis at birth is in the scrotum in order to provide the temperature differential essential for normal spermatogenesis. Appropriate screening programmes and early surgical intervention are the prerequisites to ensure optimal fertility in adulthood and a con...

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Male Infertility and Variation in CAG Repeat Length in the Androgen Receptor Gene: A Meta-analysis

Abstract: This meta-analysis provides support for an association between increased androgen receptor CAG length and idiopathic male infertility, suggesting that even subtle disruptions in the androgen axis may compromise male fertility.

Cited by 123 publications

References 52 publications

Effect of smoking on semen quality, FSH, testosterone level, and CAG repeat length in androgen receptor gene of infertile men in an Indian city

Effect of smoking on semen quality, FSH, testosterone level, and CAG repeat length in androgen receptor gene of infertile men in an Indian city

Could androgen receptor gene CAG tract polymorphism affect spermatogenesis in men with idiopathic infertility?

Factors controlling testis descent

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