Scott WW. What Makes the Prostate Grow. J Urol. 1953;70:3:477-88.
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| William Wallace Scott, MD |
Dr. Scott opens by stating,
"Understanding fully that we don't know precisely what makes the prostate grow, I shall endeavor to outline what might be considered the present status of the problem and, if time permits, indulge in a little biological extrapolation."Throughout his speech, Scott describes a variety of animal experiments that demonstrate the effects of endocrine manipulation of prostatic size, histology and function. He credits the residents of the Brady with most of the work.
He starts with embryology and works through the natural history of prostate growth. Scott notes that placental male mammals are the only animals born with prostates. In the final trimester of pregnancy, the prostate undergo dramatic changes in epithelial content – a change believed to occur under the influence of gonadal hormones as the timing coincides with changes in the breast, uterus and vagina of female animals. After birth, the prostate regresses, not repeating the changes observed in the last trimester until puberty, when the maturing testes gain hormonal function. The prostate remains dormant until a number of decades later, when nodular hyperplasia and carcinoma can develop. Based on these data, Scott believed "the best working hypothesis is that both benign hyperplasia and cancer of the prostate results from a disturbance of the ratio and quantity of androgens and estrogens in older men."
To support his argument, Dr. Scott reviews the effects of castration on the adult prostate. It was well-established that castrating a variety of animals (bulls, dogs, and mice) results in a small, firm and fibrotic prostate that lost the ability to create prostatic secretions. It was commonly believed at the time, that castration resulted in androgen withdrawal and without androgen stimulation, the prostate would regress. Scott felt this supposition was wrong – or at least unsupported by the existing evidence. While the exact role of the Leydig and Sertoli cells were unknown, Scott felt that there was adequate evidence that a preponderance of once cell type could lead to an androgen-like (masculinizing) or estrogen-like (feminizing) phenotype, respectively; and he believed loss of androgens did not tell the complete story of prostatic growth. To test this hypothesis, he gave testosterone and estrogen in a variety of animal experiments. He was able to demonstrate:
- Re-growth of prostatic tissue after castration if the animal was challenged with testosterone
- Restoration of secretory function after castration with testosterone replacement
- Conflicting results demonstrating both prostate growth and shrinkage with exogenous estrogen administration
- Estrogen supplementation after castration can result in prostate growth
- Estrogen supplementation did NOT counteract testosterone replacement in the castrate animal, leading to prostatic growth after castration
In addition, it was well-known that the liver metabolized estrogens, but its role in androgen metabolism was not known. Scott provided evidence that the liver is a "physiologic filter" for testosterone, inactivating the androgen and leading to feminizing effects. In an elaborate surgical experiment, Drs. Grayhack and Harris (residents at the Brady) created an adrenal shunt in dogs so that adrenal androgens would first pass through the liver, effectively removing all systemic androgen from circulation (see figure).
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| An "experimental" shunt by Drs. Grayhack and Harris, very different from what most urologists know as today as the Grayhack shunt. The surgery demonstrated in the figure shunts blood from the adrenal directly into the portal circulation as an experimental treatment for castrate-resistant prostate cancer. |
In summation, this is a fascinating piece collating and synthesizing the data regarding hormones and prostatic growth 12 years after the seminal work by Huggins and Hodges.[1]
To read the entire manuscript: follow the link above, visit the Centennial Website or here.
HISTORICAL CONTRIBUTIONS highlight the greatest academic manuscripts from the Brady Urological Institute over the past 100 years. As the Brady Urological Institute approaches its centennial, we will present a HISTORICAL CONTRIBUTION from each of the past 100 years. In the most recent experience, the most highly cited article from each year is selected; older manuscripts were selected based on their perceived impact on the field. We hope you enjoy!
[1] 1. Huggins, C., and Hodges, C. V.: Studies on Prostatic Cancer: I. The Effect of Castration, of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate, Cancer Research 1:293, 1941.