USRF Research

Androgen Deprivation Treatment
Part I. History

Leonard S. Marks, M.D.
Medical Director, USRF

Androgens nourish the prostate. (Source: JD McConnell, Monogr. Urol. 11(1), 1990.)

2nd Quarter, 2001 - The prostate gland is an androgen-dependent organ. Testosterone (T)---and the intracellular metabolite dihydrotestosterone (DHT)---are the primary substances responsible for prostate growth and maintenance. Without the testosterone outpouring of puberty, the prostate gland does not develop. Without the continuing trophic influence of T and DHT in adults, prostate growth stops, and atrophy ensues. Moreover, prostate cancer usually regresses when a castrate status is induced, thus the advent in 2001 of two new testosterone-lowering products---Abarelix and the Viadur implant---and the continuing interest in androgen-deprivation therapy.

Awareness of the androgen-dependence of prostate tissue can be traced back to the work of John Hunter, the Scot known as the father of scientific surgery, who observed in 1786 that castrated bulls had small prostates:

(Source: Hunter, J. : Observations on Certain Parts of the Animal Oeconomy. In: Palmer J.F., ed. The complete works of John Hunter. Vol. 4. Philadelphia: Haswell, Barrington, and Haswell; 1841: 68.)

"The prostate gland, Cowper's glands, and the glands along the urethra in the perfect male are large and pulpy…while in the castrated animal they are small, flabby, tough and ligamentous, and have little secretion…."

One hundred years later, castration was used in the U.S. with variable success as a treatment for urinary retention associated with prostate enlargement (White, J.W.: The results of double castration in hypertrophy of the prostate. Ann. Surg., 22: 1, 1895;    Cabot, A.T. : The question of castration for enlarged prostate. Ann. Surg. , 24: 265, 1896).

The above observations notwithstanding, it was the work of urologist Charles B. Huggins (1901-1997) who first applied scientific method to the study of androgen-prostate relationships, earning him the Nobel Prize in Physiology and Medicine in 1966. The Huggins work, performed in the late 1930s and early 1940s along with his students, W. W. Scott and Clarence V. Hodges, has been deemed the most important body of urological research in history. When Huggins was awarded his Prize, the Nobel committee said:

"Your fundamental discoveries concerning the hormone dependence of normal and neoplastic cells in experimental animals and their immediate practical application to the treatment of human prostatic and breast cancer have already given many years of an active and useful life to patients with advanced cancer over the entire civilized world, patients who would have been lost to all other forms of therapy."

In his official University of Chicago obituary, Huggins is quoted as remembering distinctly how he felt the day "we knew for sure that we had learned how to treat advanced prostate cancer. That night I walked home---one mile---and I had to sit down two or three times, my heart was pounding so. I thought, 'This will benefit man forever…A thousand years from now people will be taking this treatment.'" To date, 60 years into Huggins' millenium, that prediction may well prove to be correct. The significance of Huggins' work is explained here.

The Huggins discovery and the Hunter observations have found independent confirmation in three colorful areas of special interest: (1) the eunuchs of China, who were raised to guard the emperor's harem, (2) the castrati singers of Italy, who were raised to sing alto in the church choir and (3) the guevedoces (literally, "penis at 12") of the Dominican Republic, who through an inherited deficiency of the enzyme 5-alpha reductase, lived into adulthood with undeveloped prostates. Detailed study of the latter group eventually led to discovery of the drug, finasteride (Proscar), now used throughout the world to treat men with symptomatic benign prostatic hyperplasia. A USRF study published in 1997 first clarified the effects of finasteride on prostate tissue of man.


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