molinterv.aspetjournals.org/cont … 3.full.pdf
Androgens are essential for male development and the maintenance of male secondary
characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis.
The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic
properties. The recent discovery of nonsteroidal selective androgen receptor modulators
(SARMs) provides a promising alternative for testosterone replacement therapies with
advantages including oral bioavailability, flexibility of structural modification, androgen receptor
specificity, tissue selectivity, and the lack of steroid-related side effects.
Prostate
In the prostate, testosterone is rapidly converted to DHT by type
2 5α-reductase. Conversion to DHT amplifies the action of testosterone
by 3–5 fold, owing to the greater binding affinity of DHT
(as compared to testosterone) to the AR (15). DHT plays a critical
role in determining prostate size prior to and during adulthood
and is believed to be essential for the development of benign prostate
hyperplasia (BPH), which occurs in 50% and 90% of men in
their fifties and nineties, respectively, in the United States. The
major problem associated with BPH is lower urinary tract symptoms
(LUTS). Multiple lines of evidence suggest the importance of
androgen, especially DHT, in the development of BPH. For instance,
BPH does not develop in males with certain type 2 5α-reductase
mutations or in males with very low levels of androgen due to
prepubertal castration or hypopituitarism-related hypogonadism
(16). [u]Moreover, clinical treatment of BPH either by chemical or
surgical castration, or with a type 2 5α-reductase inhibitor (e.g.,
finasteride) induces apoptosis of epithelial cells, which in turn
significantly decreases the volume of the prostate /u. Recently,
the role of age-dependent changes in the intraprostatic hormonal
environment in the development of BPH was evaluated. Despite the
aging-related decrease in testosterone and intraprostatic DHT production,an increased estradiol–DHT ratio was found in the transition zone of aging human prostate. This relative estrogen-dominant
status was believed to be relevant to the development of BPH (18).
Furthermore, estradiol is capable of inducing precancerous lesions
and prostate cancer in aging dogs (19). Therefore, testosterone supplementation
in older men raises concern with regard to acceleration
of BPH and/or prostate cancer.