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ANDROGENS, THE PROSTATE AND THE CONSEQUENCES OF NEOPLASIA
Feneley, M.R.
Senior Lecturer in Urologic Oncology, Institute of Urology, University
College London Hospitals
Prostate cancer is the second commonest cause of death from malignancy
in men, after lung cancer. Its rising incidence, due
not least to PSA screening, has contributed to the
realisation that this is the commonest non-cutaneous
malignancy affecting men in most industrialised countries.
Yet many more men have the disease in an asymptomatic
form than are treated for it or die from it. The sensitivity
of prostate cancer to endocrine manipulation described
by Huggins in 1941 still represents the most significant
therapeutic advance in the past 60 years. Anti-androgen
therapy remains the first line treatment for locally
advanced and metastatic cancer. It is not however
required for organ-confined prostate cancer, other
than in neoadjuvant and adjuvant settings (i.e. in
combination with other definitive treatment). Ongoing
advances in the detection of prostate cancer in its
early stages enable potentially curative treatment
to be offered, particularly to men at greatest risk
of dying from this disease, with the benefit of long-term
disease-free survival. Microscopic foci of prostate
cancer are common, increasingly so with advancing
age. Only a small proportion of such tumours will
acquire the potential to develop into life-threatening
disease, and symptoms are rare under the age of 50
years. The histological diagnosis can be made from
biopsies following PSA screening. However, many men
do not undergo screening and will be at risk from
the progressive tumours. It is not yet possible to
distinguish reliably the indolent from the aggressive
tumours by histological findings alone. Further research
into the molecular mechanisms of malignant progression
may enable disease progression to be predicted in
the future. Manipulation of prostatic androgen activity
with 5 alpha-reductase inhibitors is known to alter
the risk of cancer diagnosis on biopsy, and its histological
assessment. However, such pharmacological manipulation
of tissue testosterone and dihydrotestosterone levels
may not be safe in the long-term for all men. This
may apply particularly to the ageing prostate previously
exposed to carcinogenic initiators. There is no evidence
that physiological testosterone levels initiate prostate
cancer. 5 alpha-reductase inhibition induces opposite
effects on tissue testosterone and dihydrotestosterone
levels. The distinct activities of these two hormones
in respect to normal androgen signalling and to their
effects on prostate cancer may in fact promote growth
of those early prostate tumours that have already
acquired the molecular disturbances to sustain progression.
With growing understanding of the influence of stroma
on the malignant phenotype and the dependence of normal
epithelial differentiation on stromal androgen activity,
a protective effect of physiological androgen signalling
on prostate health may be considered. Early events
in prostatic carcinogenesis present a tumour profile
very different from that selected by metastatic progression
and androgen deprivation. For patients on testosterone
supplementation who have been appropriately pre-screened,
clinical monitoring can assure that with any future
tendency towards malignancy the diagnosis is established
early, perhaps more promptly than otherwise, and at
a stage that is frequently curable by definitive non-endocrine
treatment. The role of androgens and androgen signalling
pathways in the prostate will be considered in relation
to the development and progression of malignancy,
with particular reference to the safety of testosterone
replacement therapy with prostate monitoring. The
importance of PSA testing and screening for prostate
cancer in assuring prostate health will be emphasised.
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