الفهرس 
ANDROGENOnly 14 pages are availabe for public view
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Abstract
Androgens are important hormones for expression of the male phenotype. They have characteristic role during male sexual differentiation, development and maintenance of secondary male characteristics and during initiation and maintenance of spermatogenesis. The two most important androgens in this respect are T and DHT, which belong to the group of steroid hormones. The major circulating androgen is T, which is synthesized from cholesterol in the Leydig cells in the testis.
Testosterone is secreted at adult levels during 3 epochs of male life, transiently during the first trimester of intrauterine life, during neonatal life and continually after puberty to maintain virilisation. T circulates in blood at concentrations above its aqueous solubility by binding to circulating plasma proteins.
Dihydrotestosterone has higher binding affinity to the AR and 3-10 fold greater molar potency than T. T is converted to the most potent natural androgen, DHT, by the 5α reductase enzyme. The diversification pathway involves T being converted to estradiol to activate ERs.
The primary mechanism of biological androgen action is initiated by the binding of T or its analogs to the AR causing its activation, which is specified by a single gene located at Xq11-12 that specifies a protein of 919 amino acids which resides in the nucleus.
The current model for androgen action involves a multi step mechanism. Upon entry of T into the androgen target cell, binding occurs to the AR either directly or after its conversion to DHT. Binding to the receptor is followed by dissociation of HSPs in the cytoplasm, accompanied simultaneously by a conformational change of the receptor protein resulting in transformation and translocation to the nucleus.
The skin locally synthesizes significant amounts of sexual hormones, with sebaceous and sweat glands being the major contributors. Human genital skin fibroblasts contain both the full-length 110 KDa AR protein (AR-B) and an 87 KDa N-terminally truncated AR isoform (AR-A). High AR levels were present in male and female reproductive tissues from mid-trimester fetuses, including penis, prostate, testis, epididymis, scrotal skin, labial skin, uterus/cervix and ovary.
The major domains of AR include NTD, HR, DBD and LBD. DBD and LBD have a high homology with the corresponding domains of the other members of the steroid receptor family, unlike NTD. A poly-glutamine stretch, encoded by a polymorphic (CAG) nCAA repeat is present in the NTD. The length of the repeat has been used for identification of X-chromosomes for carrier detection in pedigree analyses.
Several types of mutations have been found in the AR and linked to endocrine dysfunctions, just like the polymorphism involving the polyglutamine tract in NTD. In general in 70% of the cases, AR gene mutations are transmitted in an X-linked recessive manner, but in 30% the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms.
Over 300 point mutations in the AR gene have been found to cause AIS. The great majority impairs DNA or androgen binding and cause CAIS or PAIS, a small number have been proven to cause MAIS.
The main phenotypic characteristics of individuals with CAIS are: female external genitalia, a short blind ending vagina, absence of Wolffian duct derived structures and the absence of a prostate, the absence of pubic and axillary hair and the development of gynecomastia. Usually, elevated or normal T levels and elevated LH levels are found. They typically present either before puberty with masses in the inguinal canal that are subsequently identified as testes or at puberty with primary amenorrhea and sparse to absent pubic or axillary hair. Breasts and female adiposity develop normally. Sexual identity and orientation are unaffected.
PAIS individuals have signs of external genital masculinization including clitoromegaly or posterior labial fusion. Gynecomastia at puberty and impaired spermatogenesis occur in all individuals with PAIS. Pubic hair is usually moderate; facial, body, and axillary hair are often reduced. In PAIS, several phenotypes ranging from individuals with predominantly a female appearance or persons with ambiguous genitalia to individuals with a predominantly male phenotype (Reifenstein syndrome) have been detected. Determining the sex of rearing may be an issue for children with frank genital ambiguity.
The external genitalia of MAIS individuals are unambiguously male. They usually present with gynecomastia at puberty. They may have undermasculinization that includes sparse facial and body hair and small penis, impotence may be a complaint and spermatogenesis may or may not be impaired.
The length of the polyglutamine repeat is inversely proportional to the degree of normal functionality of the AR. This observation has led to the hypothesis that longer polyglutamine tracts might possibly be considered a risk factor for male infertility, bearing in mind that the CAG repeat variation is a naturally occurring polymorphism within the AR. It was noted that males with >26 repeats had a 4 times greater risk of being azoospermic.
AR gene mutations have also been associated with cancers and PCa in particular. Congenital AR dysfunction or deficiency of 5-alpha-reductase in genetic males causes minimal or absent development of the prostate gland. Early PCa usually causes no symptoms. Sometimes PCa does cause symptoms, often similar to those of benign prostatic hypertrophy. Genetic variations in the AR that affect its activity have been shown to affect PCa risk. Shorter CAG repeat length in NTD is associated with the occurrence of more aggressive PCa, earlier age of onset and likelihood of recurrence.
A direct relationship was found between AR mutations and some male specific phenotypes as: risk factors for coronary heart disease, perineal hypospadias, male breast cancer, TC, AGA and HCC. There was no correlation between AR and male sexual orientation.
Concerning female phenotypes, no association was found with hirsutism in females with or without hyperandrogenemia. An association was found with PCO, increased risk for precocious pubarche and subsequent ovarian hyperandrogenism and possibly a role in breast cancer.
Expansion of the polyglutamine tract to more than 40 CAG repeats causes Kennedy disease with some symptoms of MAIS. Clinical symptoms usually manifest in the third to fifth decade and result from severe depletion of lower motornuclei in the spinal cord and brainstem.
Some AR mutations remain silent and show no phenotypic abnormalities, and this is presented widely in the population.
A database of AR gene mutations was described in 1994, which included 114 unique mutations. In 1996, another version of AR mutation database was described, which contained 212 entries representing 239 patients with androgen insensitivity or PCa. In 1997, the number of reported mutations in the database had risen from 212 to 272. In 2004, it was stated that the reported mutations had risen to 605.
Further research is required for more understanding of the AR mutations, their evolution and their various effects on different phenotypes, how to guard against them, further understanding of early warning signs, raising the public awareness and finally therapeutic trials in order to reverse the evolving phenotype through gene therapy.