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Endocrinology of Benign and Malignant Prostate Disease in Aging

E-Newsletter No. 35

Benign prostatic hyperplasia (BPH) and prostate cancer (CaP) are two common diseases affecting aging men. Mortality rates for BPH are <0.5/100,000 population, but this disease affects the quality of life and health care costs exceed 4 billion dollars/year. It is estimated that CaP will be diagnosed in 179,000 American men, and it will cause 37,000 deaths in 2002.

The development, growth, and differentiation of the normal prostate are regulated by androgens, and these effects are mediated by the androgen receptor (AR). The concept that normal androgen production and normal ARs are required for normal prostate development is based upon the following observations: 

Puberty is associated with an increase in serum testosterone (T) and prostate volume; 
Abnormal androgen biosynthesis and inactivating mutations of the AR and the 5a-reductase type II genes are associated with rudimentary development of the prostate in 46 XY individuals; 
BPH and CaP have not been observe in males who were castrated around the age of puberty;
Androgen can induce prostate enlargement or cancer in susceptible animals.

Autopsy and population based studies of prostate volume indicate that mean prostate volume increases during puberty, is stable from age 20 to 50, and then increases. Prostate volumes in Japanese and Chinese men are less than those in Caucasian men.

The prevalence of clinical CaP and mortality rates vary greatly among ethnic groups. They are higher in African-Americans (224 and 55/100,000 persons/year, intermediate in Caucasians (150 and 24/100,000) and lower in Orientals living in Asia (82 and 10/100,000). However, autopsy studies indicate greater prevalence of latent CaPs and less variation among ethnic groups. Latent prostate cancers are present in 10-20% of prostates from men in their thirties, and they are nearly universal in prostates of 90-year-old men.

The possibility that differences in sex steroid hormone levels could account for differences in prostate volume and CaP among ethnic groups has encouraged investigators to assess hormonal levels in different ethnic groups. It appears that African- American fetuses are exposed to somewhat higher levels of T than Caucasian fetuses. Additionally, young adult African-American men have higher mean serum levels of T than age-matched Caucasian-American men. Levels in young Japanese men are similar to Caucasians. Differences in serum T and dihydrotestosterone (DHT) between Caucasians living in Pennsylvania and Chinese living in Beijing are not due to differences in 5a-reductase activity, but rather to dietary effect on androgen substrates. No differences in T levels or metabolism were noted between Chinese and Caucasians living in Pennsylvania.

Androgens appear to facilitate the development of BPH and CaP, but available evidence provides little evidence that men who develop either disease have higher serum levels of T or DHT at the time of diagnosis or even 10 years prior to the diagnosis. The lack of differences in circulating levels of T and DHT has caused investigators to search for differences in other components of the androgen-signaling pathway.

Differences in prostatic 5a-reductase type II activity and mutations of this enzyme, prostatic level of DHT, AR levels and mutations of the AR, and microsatellites of the AR that affect transcriptional activity have been studied in BPH and CaP. Decreased CAG repeat length is associated with increased risk of prostate surgery for prostate enlargement. Mutations of the AR are rare in primary CaP, but shorter poly-Q repeats are associated with increased risk of developing CaP.

Anti-hormonal therapy is used to treat both BPH and CaP. Inhibition of 5a-reductase reduces prostate volume about 20% and is only modestly effective in treating mild or moderated lower urinary tract symptoms. Androgen ablation induces a remission in up to 80% of men with metastatic CaP, but usually it is sustained for less than 2 years. Preventive therapy with 5a-reductase inhibitors may be more effective than treating established disease with anti-androgen therapy.

These partial responses of BPH and CaP to anti-hormonal therapy make one cautious in providing androgen replacement to androgen deficient, aging men who may have mild or moderate BPH or latent CaP. However, the increasing prevalence of androgen deficiency with aging and the beneficial effects of androgen replacement on skeletal muscle, bone mineral density and libido make it critical that we better assess the risk:benefit ratio of androgen replacement therapy in aging men. 

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