T

Number of CAG triplets (normal range 9-37)

COOH

AR protein

Encoded polyglutamine stretch (variable length acc. to number of CAG triplets)

Fig. 3.1 Display of the X-chromosome with the androgen receptor (AR) gene. Exon 1 contains a variable number CAG repeats encoding a polyglutamine stretch of variable length in the receptor protein. The number of CAG repeats or length of polyglutamine residues is inversely associated with the transcriptional activity of androgen-dependent genes, hence androgen effects in target tissues.

2000; Quigley et al. 1995), maleness maybe described as the sublimate of gender difference. Testosterone and its metabolite dihydrotestosterone (DHT) exert their effects on gene expression via the AR. A diverse range of clinical conditions starting with complete androgen insensitivity (CAIS) has been correlated with mutations in the AR (Hiort etal. 1996; Meschede etal. 2000; Quigley etal. 1995). Subtle modulations of the transcriptional activity induced by the AR have also been observed and frequently assigned to a polyglutamine stretch of variable length within the N-terminal domain of the receptor. This stretch is encoded by a variable number of CAG-triplets in exon 1 of the AR gene located on the X-chromosome (Fig. 3.1). First observations of pathologically elongated AR CAG repeats in patients with X-linked spinobulbar muscular atrophy (SBMA) showing marked hypoandrogenic traits (La Spada etal. 1991) were supplemented by partially conflicting findings of clinical significance also within the normal range of CAG repeat length. The mod-ulatory effect on androgen-dependent gene transcription is linear and probably mediated by a differential affinity of coactivator proteins to the encoded polyglutamine stretch, such as ARA24 and p160 (Hsiao et al. 1999; Irvine et al. 2002). As

Bipotent Gonad

LH/hCG

46,XY i

DAX-1

SOX-9

DMRT1 and 2

StAR

P450scc

P450c17

46,XY i

DAX-1

SOX-9

DMRT1 and 2

Leydig Cells

Sertoli cells

Testosterone 5a-Reductase ^

Dihydrotestosterone

Androgen receptor

Inhibin B Anti-Müller Hormone

Regression of Mullerian remnants

Virilization

Fig. 3.2 Pathways of human sexual differentiation. The genetic cascade for testicular development first leads to initiation of a bipotent gonad before the testis is determined. Within the testis, the Leydig cells synthesize testosterone via five enzymatic steps from cholesterol which is secreted to react peripherally via the androgen receptor after being at least partially converted to dihydrotestosterone. The Sertoli cells synthesize anti-Mullerian hormone which is necessary for regression of Mullerian ducts.

these proteins are ubiquitously but nevertheless non-uniformly expressed, the modulatory effect of the CAG repeat polymorphism on AR target genes is most likely not only dependent on androgenic saturation and AR expression, but also varies from tissue to tissue. To date, an involvement of prostate cancer risk, spermatogenesis, bone density, hair growth, cardiovascular risk factors and psychological implications has been demonstrated.

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