marmaramedicaljournal.org/text.php3?id=557
Abstract
This review presents the androgen receptor gene and its clinical importance in gynecology, oncology and infertility. A computerized literature search through Medline and PubMED was performed, applying the word " androgen receptor " cited between the year 1990 and 2009. The androgen receptor mediates androgen action, determining male sexual phenotypes and spermatogenesis. Constitutional mutations in the androgen receptor cause various forms of male pseudohermaphroditism. The androgen receptor CAG repeat length variations is associated with risk for some cancers, pelvic organ prolapsus, osteoporosis, hyperandrogenism in polycystic patients, metabolic syndrome and male infertility (Spinal bulbar muscular atrophy). Genetic diagnosis and research is becoming a standard requirement for the clinical practice of reproductive medicine, gynecology and oncology
ANDROGEN INSENSITIVITY SYNDROMES (AIS)
Constitutional mutations in the AR impair androgen - dependent male sexual differentiation to various degrees and cause various forms of male pseudohermaphroditism known as AIS. AR mutations that severely impair the amount, structure or function of the AR cause the well-known complete AIS (CAIS) (testicular feminizing syndrome), evidenced by the complete feminization of 46 XY individuals at birth. This condition has an incidence of 1in 20000 to 1in 60000 males and it is transmitted as an X-linked trait8-11.
Mutations that do not completely disrupt AR function cause partial AIS (PAIS), in which various degrees of ambiguous genitalia occur, including partial labialscrotal fusion, hypospadias and gynaecomastia. Subtle mutations that result in minimal AR dysfunction lead to minimal AIS where depressed spermatogenesis occurs without any abnormalities in the secondary male sexual characteristics12.
The development of the gonadoblastoma has been associated with a Y chromosome gene, in dysgenetic gonads. Codon 607 mutation in the DNA-binding domain of the AR gene in CAIS may be associated with an increased risk of the early development of a germ cell tumour13-15.
Trinucleotide repeat disorders (trinucleotide repeat expansion disorders, triplet repeat expansion disorders or codon reiteration disorders) are caused by an expansion of repetitive three bases in the causative gene. In over half of these disorders the repeated codon is CAG, and codes for glutamine (Q). These diseases are commonly referred to as polyglutamine (PolyQ) diseases. The remaining disorders are classified as:
1)Non-polyglutamine diseases:
1)Fragile X syndrome (CGG repeat )
2)Myotonic Dystrophy (CTG repeat )
3)Friederich’s Ataxia (GAA repeat )
2)Polyglutamine (PolyQ) diseases:
1)Spinal and bulbar muscular atrophy
2)Huntington’s disease
3)Dentatorubralpallidoluysian atrophy (DRPLA)
4) Five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7).
These disorders are characterized by an autosomal dominant mode of inheritance (with the exception of spino-bulbar muscular atrophy which shows X-linked inheritance), midlife onset, a progressive course, and a correlation of the number of CAG repeats with the severity of disease and the age at onset. These disorders likely share a common pathogenesis caused by the gain of a toxic function of the expanded polyglutamine tract and neurodegeneration16.
SELECTIVE ANDROGEN RECEPTOR MODULATORS(SARMs)
SARMs are a novel class of AR ligands, which bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. With improved pharmacokinetic characteristics and tissue-selective pharmacological activities, SARMs are expected to greatly extend the clinical applications of androgens. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer and end-stage renal disease, male contraception, endometriosis, hypogonadism, functional limitations associated with aging and chronic disease, frailty and osteoporosis50