Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

In 1941, Huggins and Hodges reported that androgen ablation therapy causes regression of primary and metastatic prostate cancer [1]. Approximately 20-40% of patients treated with radical prostatectomy will have tumor recurrence and elevation of serum prostate-specific antigen (PSA) [2]. Primary metastatic sites for prostate cancer include bones and lymph nodes. More than 80% of patients who die from prostate cancer develop bone metastases [3-5]. Androgen ablation therapy is provided to patients who develop recurrent or metastatic prostate tumors. However, 80-90% of the patients who receive androgen ablation therapy ultimately develop recurrent castrate-resistant tumors 12-33 months after androgen ablation therapy. The median overall survival of patients after tumor relapse is 1-2 years [6,7]. Several long-term studies have failed to show that androgen ablation therapy provides a disease-specific survival advantage in patients [6]. Androgen ablation therapy is associated with undesired side-effects that impair the patient's quality of life as well as increased risk of diabetes and cardiovascular diseases [6]. Therefore, shortening the period of androgen ablation therapy may protect the patients.Androgens are male sex hormone and include several steroids, such as testosterone, dehydroepiandrosterone, androstenedione, androstenediol, androsterone, and dihydrotestosterone (DHT). 90-95% of androgens are produced by the testes, while some androgens are produced in the adrenal glands. Testosterone is the main circulating androgen in human body, while DHT is a more potent androgen that has 5-fold higher affinity for the androgen receptor (AR) than does testosterone [7-9]. When testosterone enters prostate cells, 90% is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase [9].The average serum testosterone level declines with age and elderly men usually have the condition as partial androgen deficiency. It decreases from approximately 620-670 ng/dl at age 25-44