Effect on development In some cell types, testosterone interacts directly with androgen receptors, whereas, in others, testosterone is converted by
5-alpha-reductase to
dihydrotestosterone (DHT), an even more potent
agonist for androgen receptor activation. Testosterone appears to be the primary androgen receptor-activating hormone in the
Wolffian duct, whereas dihydrotestosterone is the main androgenic hormone in the
urogenital sinus,
urogenital tubercle, and
hair follicles. Testosterone is therefore responsible primarily for the development of male
primary sexual characteristics, whilst dihydrotestosterone is responsible for
secondary male characteristics. Androgens cause slow maturation of the bones, but more of the potent maturation effect comes from the
estrogen produced by
aromatization of androgens.
Steroid users of teen age may find that their growth had been stunted by androgen and/or estrogen excess. People with too little sex hormones can be short during puberty but end up taller as adults as in
androgen insensitivity syndrome or
estrogen insensitivity syndrome.
Knockout-mice studies have shown that the androgen receptor is essential for normal female fertility, being required for development and full functionality of the
ovarian follicles and
ovulation, working through both intra-ovarian and
neuroendocrine mechanisms.
Maintenance of male skeletal integrity Via the androgen receptor, androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling can be attributed to both
osteoblasts and
osteocytes.
Role in females The AR plays a role in regulating female sexual, somatic, and behavioral functions. Experimental data using AR
knockout female mice, provides evidence that the promotion of cardiac growth, kidney hypertrophy, cortical bone growth and regulation of
trabecular bone structure is a result of DNA-binding-dependent actions of the AR in females. Moreover, the importance of understanding female androgen receptors lies in their role in several genetic disorders including androgen insensitivity syndrome (AIS).
Complete (CAIS) and
partial (PAIS) which are a result of
mutations in the genes that code for AR. These mutations cause the inactivation of AR due to mutations conferring resistance to circulating testosterone, with more than 400 different AR mutations reported.
Mechanism of action Genomic The primary mechanism of action for androgen receptors is
direct regulation of
gene transcription. Androgens (also called androgenic hormones), such as testosterone or dihydrotestosterone, are understood to exert their primary effects through binding to an androgen receptor in the
cytosol. The receptor is translocated to the nucleus upon androgen binding and ultimately results in the transcriptional regulation of a number of genes via androgen responsive elements. This androgen response mechanism is perhaps best known and characterized in the context of male sexual differentiation and puberty, but plays a role in a variety of tissue types and processes. Upon binding to androgens, the androgen receptor dissociates from accessory proteins, translocates into the nucleus, dimerizes, and then stimulates transcription of androgen-responsive genes. The binding of an androgen to the androgen receptor results in a
conformational change in the receptor that, in turn, causes dissociation of
heat shock proteins, transport from the
cytosol into the
cell nucleus, and
dimerization. The androgen receptor dimer binds to a specific sequence of DNA known as a
hormone response element, where it forms macromolecular protein condensates that might facilitate rapid gene regulation as consequence of local high protein concentrations together with other coregulators. Androgen receptors interact with other proteins in the nucleus, resulting in up- or down-regulation of specific
gene transcription. Up-regulation or activation of transcription results in increased synthesis of
messenger RNA, which, in turn, is translated by
ribosomes to produce specific proteins. One of the known target genes of androgen receptor activation is the
insulin-like growth factor 1 receptor (IGF-1R). Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior. One function of androgen receptor that is independent of direct binding to its target DNA sequence is facilitated by recruitment via other
DNA-binding proteins. One example is
serum response factor, a protein that activates several genes that cause muscle growth. Androgen receptor is modified by
post-translational modification through
acetylation, which directly promotes AR-mediated
transactivation,
apoptosis and contact-independent growth of
prostate cancer cells. AR acetylation is induced by androgens and determines recruitment into
chromatin. The AR acetylation site is a key target of
NAD-dependent and
TSA-dependent
histone deacetylases
Non-genomic More recently, androgen receptors have been shown to have a second mode of action. As has been also found for other
steroid hormone receptors such as
estrogen receptors, androgen receptors can have actions that are independent of their interactions with DNA. Androgen receptors interact with certain
signal transduction proteins in the cytoplasm. Androgen binding to cytoplasmic androgen receptors can cause rapid changes in cell function independent of changes in gene transcription, such as changes in
ion transport. Regulation of signal transduction pathways by cytoplasmic androgen receptors can indirectly lead to changes in gene transcription, for example, by leading to phosphorylation of other transcription factors. == Genetics ==