Androgen receptor gene GGN and CAG polymorphisms among severely oligozoospermic and azoospermic Swedish men

Ruhayel, Yasir; Lundin, Kristina; Giwercman, Yvonne Lundberg; Halldén, Christer; Willén, Marianne; Giwercman, Aleksander

doi:10.1093/humrep/deh349

Cited by 54 publications

(59 citation statements)

References 49 publications

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“…For example, short GGN repeats have been associated with lower semen volume (Lundin et al, 2006), whereas increased GGN repeat length has been observed among boys with penile hypospadias and in men with cryptorchidism (Aschim et al, 2004;Radpour et al, 2007). Both we (Lundin et al, 2003) and others (Rajender et al, 2006;Tut et al, 1997) reported no significant differences in distributions of GGN repeat lengths between infertile and fertile men, while in other studies an association between GGN repeat length and infertility was observed only in combination with certain CAG repeat lengths (Ferlin et al, 2004;Ruhayel et al, 2004).…”

Section: Introductioncontrasting

confidence: 43%

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Non-linear association between androgen receptor CAG and GGN repeat lengths and reproductive parameters in fertile European and Inuit men

Brokken¹,

Rylander²,

Jönsson³

et al. 2013

Molecular and Cellular Endocrinology

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Recently the dogma that there is an inverse linear association between androgen receptor (AR) CAG and GGN polymorphisms and receptor activity has been challenged. We analysed the pattern of association between 21 male reproductive phenotypes and AR CAG/GGN repeat lengths in 557 proven--fertile men.A linear association was only found between sperm DNA fragmentation index (DFI) and CAG length, and between inhibin B and GGN length. Men with longer CAG then the reference (22--24), had higher oestradiol levels, whereas men with shorter CAG stretches had a higher DFI and a higher proportion of Fas--positive germ cells. Subjects with either short or long CAG had increased seminal levels of prostate--specific antigen and neutral α--glucosidase activity. Compared to men with the median GGN length of 23, those with shorter GGN repeats had higher levels of inhibin B, higher proportions of normal and progressive sperm, and a higher fraction of Fas--positive sperm, while men with longer GGN had higher oestradiol levels.These data indicate that at least for some markers of male reproductive function the association with CAG or GGN repeat length is curvilinear.

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Section: Introductioncontrasting

confidence: 43%

“…Ruhayel et al (2004) reported low prostate marker concentrations in infertile men with 24 GGN repeats as compared to men with the median length of 23 repeats. Lundin et al (2006) showed that, compared to men with ≥23 GGN repeats, men with short GGN length (< 23) had lower semen volume and semen fructose levels.…”

mentioning

confidence: 93%

Non-linear association between androgen receptor CAG and GGN repeat lengths and reproductive parameters in fertile European and Inuit men

Brokken¹,

Rylander²,

Jönsson³

et al. 2013

Molecular and Cellular Endocrinology

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“…This may lead to better management options and eventually prevention strategies for obesity and possibly lessen infertility. Androgen responsivity secondary to AR gene CAG repeat length has a multi-level influence on human reproduction and fertility through effects on male testicular development and spermatogenesis [27,28] and female pregnancy outcomes [29]. Our study further reports male stature and female weight as androgen responsive modulatory variables with potential influence on fertility.…”

Section: Discussionsupporting

confidence: 53%

“…Individuals with a lower number of CAG repeats exhibit higher AR gene expression levels and generate more functional AR receptors increasing their sensitivity to testosterone [20][21][22][23][24]. Diminished in vivo androgenicity in males leads to decreased spermatogenesis and smaller seminal vesicles [24][25][26][27] thereby impacting fertility and human reproduction [28]. AR gene CAG repeat lengths above 21 correlate with poor pregnancy outcomes in females and recurrent spontaneous abortions [29].…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor (AR) gene CAG trinucleotide repeat length associated with body composition measures in non-syndromic obese, non-obese and Prader-Willi syndrome individuals

Butler

Manzardo

2015

J Assist Reprod Genet

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Purpose Total body mass impacts reproductive health and infertility which has increased in the United States with rising rates of obesity. Overlapping genetic and environmental factors contribute to obesity and infertility including the androgen receptor (AR), a steroid hormone-activated transcription factor that is key in regulating androgen activity and sensitivity to sex hormones, weight and body composition in both males and females. The AR gene which is X-linked contains a polymorphic CAG trinucleotide repeat which varies in length and inversely correlated with gene expression. Methods We examined the AR gene CAG repeat length and measures of weight and body mass index (BMI) in 27 nonsyndromic obese and 33 lean controls and for the first time compared with 28 individuals with Prader-Willi syndrome (PWS), a rare obesity-related genetic disorder with natural sex hormone deficits to examine the effects of AR gene CAG repeat length on androgen-mediated response and obesityrelated factors relevant to human infertility and reproduction.Results Mean CAG repeat length in base pairs (278±7.9) did not significantly differ by subject group (F=2.6, p=0.08) but was strongly positively correlated with height standard deviation (SD) among males (r=0.31, p<0.05), mainly lean and obese, but not PWS (r=0.02, p=0.94). A negative correlation was observed for weight SD among females (r = −0.29, p<0.04) when grouped together. Conclusions The results were consistent with an androgenmediated effect on height and weight negligible in PWS and supporting the role of sex horomones and AR gene interaction in obesity and infertility, both cardinal features of PWS. CAG repeat length of the AR gene is a marker for increased androgen sensitivity with shorter lengths predicting smaller stature in non-PWS adult males possibly due to accelerating fusion of bone growth plates and reducing the growth phase. Increased androgen effects from shorter CAG repeat lengths in non-PWS females could impact pregnancy-related weight gain and pregnancy outcomes.

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“…To our knowledge, only 4 studies on the GGN repeat in male infertility have been conducted to date (Tut et al, 1997;Lundin et al, 2003;Ferlin et al, 2004;Ruhayel et al, 2004). Hence the functional implications of variation in the GGN repeat are unclear.…”

mentioning

confidence: 99%

No Association of Androgen Receptor GGN Repeat Length Polymorphism With Infertility in Indian Men

Rajender

Rajani

Gupta

et al. 2006

Journal of Andrology

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Androgens, acting through the androgen receptor (AR), play a role in secondary sexual differentiation from the prenatal stage to adulthood, including spermatogenesis. The AR gene has 2 polymorphic trinucleotide repeats (CAG and GGN) in exon 1. The CAG repeat length polymorphism has been well studied in a variety of medical conditions, including male infertility. Many of these studies have shown an association of the expanded CAG repeats with male infertility, although this is not true for all populations. The GGN repeat, in contrast, has been less thoroughly studied. Thus far, only 4 reports worldwide have analyzed the GGN repeat, alone or in combination with the CAG repeat, in male infertility cases. No such study has been undertaken on infertile Indian men. Therefore, we have analyzed AR-GGN repeats in a total of 595 Indian males,

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Androgen receptor gene GGN and CAG polymorphisms among severely oligozoospermic and azoospermic Swedish men

Abstract: The < 21 CAG and GGN = 23 combination of repeats may confer a lower risk of infertility to the carriers. Androgen sensitivity may be higher among carriers of the GGN = 23 allele compared to the GGN = 24 allele.

Cited by 54 publications

References 49 publications

Non-linear association between androgen receptor CAG and GGN repeat lengths and reproductive parameters in fertile European and Inuit men

Non-linear association between androgen receptor CAG and GGN repeat lengths and reproductive parameters in fertile European and Inuit men

Androgen receptor (AR) gene CAG trinucleotide repeat length associated with body composition measures in non-syndromic obese, non-obese and Prader-Willi syndrome individuals

No Association of Androgen Receptor GGN Repeat Length Polymorphism With Infertility in Indian Men

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