Side effects of androgen replacementablation in the aging male

Besides its effects upon normal and abnormal growth and physiology ofthe prostate, testosterone is also critical for maintenance of bone and muscle metabolism, as well as libido. For this reason, aging males who have an insufficient level of serum testosterone (i.e. hypogonadal males) suffer clinically from loss of bone and muscle mass as well as a decreased libido. Such aging hypogonadal males are candidates for exogenous testosterone replacement. Due to its growth-promoting effects on the prostate, however, such hormonal replacement therapy could enhance the development of BPH and/or prostate cancer. Thus, the decision to initiate such replacement hormonal therapy must be evaluated on risk vs. benefit analysis for each patient individually.

The side effects observed in naturally developed hypogonadal males are also a problem in males either at high risk of developing prostate cancer who are treated with androgen ablation therapy as a preventative modality or in patients with clinically established prostate cancer who are being given androgen ablation as therapy. In order to allow replacement hormonal therapy in hypogonadal patients and lessen side effects of such testosterone ablative therapies in patients with established prostate cancer, small molecule selective androgen response modifiers (SARMs) are being developed which retain the positive androgenic effects on bone, muscle, and libido, but which have little or no growth-stimulatory effects on the prostate. This approach is possible due to the increasing basic knowledge about the mech-anism(s) of such androgenic effects at the molecular level (Litvinov and Isaacs 2003). These molecular studies have documented that the binding of natural and synthetic SARMs induces a spectrum of conformational changes in the androgen receptor. This spectrum of conformations results in differential ability of the SARM-occupied AR to dimerize and bind to specific target genes and specific tran-scriptional cofactors inducing either stimulation or repression of transcription. Thus, the development of such SARMs will usher in an exciting time during which clinical testing will determine whether modulating testosterone's effects will have an impact on the prevention and treatment of multiple diseases of the aging male.

12.10 Key messages

• Testosterone is the major growth and functional regulator of the prostate.

• The prostate is organized functionally in stem cell units composed of stem cells, transit amplifying (TA) cells, intermediate cells and secretory luminal cells.

• Testosterone is metabolized within the prostate to both more potent androgens (i.e., DHT) and to an estrogenic metabolite (i.e., 3£ diol).

• DHT binds to the androgen receptor within prostatic stromal cells to induce the production and secretion of growth factors known as andromedins.

• Andromedins stimulate the proliferation of TA cells and the survival of TA, intermediate and secretory luminal cells (i.e., paracrine androgen axis).

• DHT binds to the androgen receptor in secretory luminal cells and directly induces the transcription of prostate differentiation markers, such as PSA, hK2 and PAP.

• Prostate cancers are derived from TA/intermediate cells. During prostatic carcinogenesis, molecular changes induce a conversion from a paracrine to an autocrine pathway so that the AR then directly stimulates the proliferation and survival of prostate cancer cells.

• Approaches to lower testosterone's stimulating abilities should have both preventative and treatment effect on prostatic cancer and BPH.

• Besides its effects upon normal and abnormal growth and physiology of the prostate, testosterone is also a critical regulator of bone and muscle metabolism, as well as libido. Therefore, therapies which reduce testosterone's effects on the development and clinical progression of either BPH or prostate cancer have major side effects upon quality of life.

• In addition, there are aging males who suffer from abnormally low serum testosterone levels with similar quality-of-life side effects. These patients can be supplemented with exogenous testosterone, but this can enhance the risk of developing BPH and prostate cancer.

• To allow replacement therapy in patients with low serum testosterone and lessen side effects of testosterone, ablative therapies in patients with established prostate cancer, small molecule selective androgen response modifiers (SARMs) are being developed which retain the positive androgenic effects on bone, muscle, and libido, but which have little or no growth stimulatory effects on the prostate.

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