Androgenic steroids are essential for the development and maintenance of the male phenotype. Testosterone, the predominant androgenic steroid hormone, is produced in testicular Leydig cells under the control of the glycoprotein hormone, luteinizing hormone (LH). Testosterone may be metabolized to the more active androgen, 5alpha-dihydrotestosterone (5alpha-DHT) or to 17beta-estradiol. Both of these metabolites play important roles in reproductive physiology: testosterone and 5alpha-DHT are essential for differentiation of the accessory sex organs and external genitalia; whereas 17beta-estradiol is critical for differentiation of sexual dimorphic nuclei in the brain. In this review we will focus on the mechanism of action of 5alpha-DHT in the male reproductive tract.

Androgen Receptor
The biological functions of androgens are mediated through the androgen receptor (AR) protein (Fig. 1). This protein binds both testosterone and 5alpha-DHT, although it has a much higher affinity for the latter. Once the steroid enters the cell and binds to the AR there is a conformational change in this protein, that causes the dissociation of several accessory proteins from the AR, including heat shock proteins. This conformational change exposes the DNA binding domain on the AR, which can then interact with specific sequences of DNA termed androgen responsive elements (AREs). AREs have been identified in the promoter and intronic regions of androgen responsive genes. Binding of the AR to an ARE has the functional property of regulating transcriptional activity of the gene.

Androgen Regulated Genes
Although the expression of many mRNAs and proteins have been described as being under androgenic control, only a few genes have been demonstrated to be regulated at the transcriptional level by androgens in vitro. These include the human prostate-specific genes PSA and hKLK2, the rat prostate-specific genes probasin and the C subunit of prostatein, and the rat liver-specific gene slp. Each of these has been shown to contain a functional ARE in either the promoter or intronic regions. Evidence for post-transcriptional regulation is also available for four secretory proteins (SVP 1-4) that are the major constituents of the seminal fluid.

The AR gene itself is regulated by androgens, although the exact mechanism has not been defined. In the majority of cases, steady-state levels of AR mRNA in androgen target tissues are increased following castration and decreased with androgen treatment. Moreover, changes in AR protein levels often parallel the response of mRNA to androgen availability . Recent evidence also suggests that transcription of the AR gene is modulated by agents acting through second messenger pathways such as cAMP.

Pathological actions of androgens
If androgens are absent or their normal route of action is blocked, then severe deficits are observed in the male physiological state. Androgen insensitivity syndrome (AIS) is caused by functional defects in the AR protein stemming from mutations affecting predominantly the steroid-binding domain or the DNA-binding domain of the AR gene. Complete AIS is distinguished by an X/Y genotypic individual with abdominal testes, absence of Wolffian derivatives and male levels of serum testosterone, who has female phenotypic characteristics including normal breast development, a blind-ending vagina and a paucity of pubic hair. This mutation emphasizes the critical necessity of a normally functioning AR in male reproductive development.

5alpha-Reductase deficiency is caused by a mutation in the enzyme 5alpha-reductase, which is responsible for converting testosterone to 5alpha-DHT. The absence of 5alpha-DHT in an X/Y genotypic individual results in a female phenotype until puberty at which time there is growth of the phallus into a penis-like organ. This phenotypic change is thought to be the result of increased availability of testosterone to bind to the AR, albeit at reduced affinity.

Although prostate cancer and benign prostate hyperplasia (BPH) are both associated with androgenic influences on the prostate, there is no evidence that androgens are directly responsible for these conditions. It is likely that androgens play a supportive role in maintaining prostatic cells in such a state that environmental, dietary or genetic insults could induce mutations of key genes such as protooncogenes or tumor suppressor genes. Thus, androgens appear to be necessary but not sufficient for these pathologic conditions.

Summary
The development and maintenance of the male phenotype is highly dependent upon the presence of the male sex steroid testosterone and its conversion to the more active androgen 5alpha-DHT. 5alpha-DHT interacts with the androgen receptor and regulates transcriptional activity of androgen responsive genes through an ARE sequence. This sequence of events regulates the synthesis of proteins which are critical for development of the male accessory sex tissues and for growth of the external genitalia.