Mechanisms involved in the development and progression of the disease

To understand prostatic growth in diseased states, it is important to understand the hormonal influences at play in normal prostate development and function. Testosterone is the primary circulating androgen in men. Within the prostate, testosterone is converted to a more potent androgen dihydrotestosterone (DHT) by the action of intracellular 5a-reductase enzymes [6]. Circulating DHT levels are low (1 : 10) when compared with testosterone, whereas in the prostate, this ratio is reversed, making DHT the primary prostatic androgen [7].

Dihydrotestosterone is essential for the development of the prostate gland. Inside the prostate, both testosterone and DHT bind to the androgen receptor (AR), stimulating the AR signalling axis that promotes cell-cycle regulation, cell survival and lipogenesis [8]. Although both the androgens are capable of binding AR, DHT has a stronger affinity than testosterone and a slower dissociation rate [9, 10]. DHT is also more potent at stimulating prostatic growth than testosterone [9]. These combined effects of DHT enhance the androgen signalling pathway in tissues where 5a-reductase enzymes are highly expressed [10].

Depending on the developmental stage of the individual, DHT signalling could promote the differentiation of the male external genitalia (gestation) or the maturation of the prostate gland (puberty) [7]. Throughout adulthood, DHT androgen signalling acts as a regulator of homoeostasis, maintaining the prostate epithelium by balancing cell proliferation and cell death [8]. Unlike testosterone, DHT does not exhibit an age-related decline in serum concentration. Some studies have shown a steady decline of testosterone every decade in healthy men [11, 12], whereas the levels of DHT either decline slightly or remain unchanged [13, 14]. It has been suggested that DHT levels remain constant in ageing individuals because the pathway of conversion from testosterone is saturated at low levels of testosterone. Morgentaler and Traish present a critical revision of the traditional view of T and PC [15]. They use a saturation model that is consistent with regression of cancer when T is reduced to castrate levels but lacks observed growth when serum T is increased. The saturation model starts from the observation that PCa growth is sensitive to variation in serum T concentrations at or below the castrate range and is insensitive to T variation above this concentration. Considering the actual interest in using T replacement therapies in men, a new definition of the relationship between T and PCa is of considerable importance. Evidence supports the hypothesis that T administration in hypogonadal men without PCa does not increase the risk for PCa growth if T levels are normalised [16-18].

Compelling evidence that implicates DHT as the primary prostatic androgen comes from the discovery of the Dominican pseudohermaphrodites or Guevedoce. This population has a deficiency in 5a-reductase and therefore their DHT levels are markedly lower, whereas their testosterone levels remain normal [19]. The prostate of these affected men is non-palpable and the prostate volume is one-tenth that of normal age-matched controls. Administration of DHT in these individuals results in prostate enlargement, strongly implicating DHT as a necessary component of prostate growth and development [20].

Androgen receptor signaling remains active even with castrate levels of serum testosterone, contrary to the previous notion that disease progression after gonadal ablation necessarily implied androgen-independent escape mechanisms. This is supproted by studies, which report high intratumoral androgens, continued AR signaling [21], and overexpression of enzymes key to androgen síntesis, which suggests that CRPC may synthesize androgens de novo [22, 23]. Until recently, available strategies that target the AR, such as antiandrogens, ketoconazole, estrogens or glucocorticoids, result in modest benefict. New drugs such as abiraterone, or MDV 3100 have shown a much more supression activity of the AR by different pathways.

The key components of DHT production are the 5a reductase enzymes. There are two well-characterised isoforms, type 1 and type 2 [24, 25]. Type 1 is present throughout all stages of life and is primarily localised in extraprostatic tissues including the non-genital skin, liver and certain brain regions. Although type 1 expression was originally thought to be absent from the prostate gland, certain studies have found type 1 within the prostatic tissue pre dominantly localised to the secretory luminal epithelium [26]. The type 2 5a-reductase isoform is prevalent in the prostatic tissue as well as the genital skin, seminal vesicle and epididymis. Although this isoform is present through all stages of prostate development, it has a single wave of expression in the skin and scalp that begins at birth and ends at ages 23 years [26]. Type 2 5a-reductase is deficient in the Guevedoce and therefore these individuals do not generate enough DHT to promote normal development of the prostate gland and the man's external genitalia [20].

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