OPTIMAL HEALTH |
The Prostate
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(To read Dr Perring's personal account of
Prostate Cancer click NEWS) Enlargement of the prostate (Benign Prostate Hyperplasia- BPH) usually commences at the age of 50, and is present, to some degree, in all men by the age of 70. It is the second commonest site, after skin, for cancer in men, and is the second commonest site of lethal cancer after the lung. Its frequency is increasing at a rate of 2-3% pa world-wide. In 1968 a 45 year old male had a 10% chance of needing his prostate removing (prostatectomy) during his lifetime - in 1997 it was 30%, mostly for BPH. Demographic projections show the number of men in Europe
over 65 will increase from 16 to 22% of the population by 2020, and the frequency of
prostate problems is likely to increase in line with the increase in the population. The development of the prostateGrowth of the prostate occurs predominantly between adolescence and the early 20s. Control of prostate size (homeostasis) is maintained by a balance between the processes of cell proliferation and cell death (apoptosis). Testosterone is necessary for prostate growth and function. Foetal testes secrete testosterone from about the eighth week of gestation and initiate prostate growth at that time. Overgrowth of the prostate does not take place from the administration of exogenous testosterone on its own - but testosterone may act as a trigger to ‘switch on’ the process (Bruchovsky 1975), and additional growth factors are necessary for the proliferation of prostate epithelial cells. These growth factors include IGF1 (the active metabolite of growth hormone), IGF2, epidermal growth factor (EGF), and keratinocytic growth factor (KGF), (Griffiths 1991) In the prostate 5a-reductase converts testosterone to dihydrotestosterone (DHT), which binds with the androgen receptor (AR) and regulates genes controlling growth of epithelial cells and PSA production. [Plasma PSA thus reflects prostate stimulation by growth factors.] It is thought that KGF stimulates the development of epithelial cells, stroma and basal cell membrane during adolescence, while in adult life growth is limited by a transforming growth factor (TGF)-b. Homeostasis is not invariably achieved, and microscopic
areas of epithelial proliferation may be seen by 25-30 years of age. At age 50
micronodular epithelial overgrowth of the cells (hyperplasia), i.e. BPH at the microscopic
level, is universally present in all races. What causes the development of clinical hypertrophy?The clinical form of BPH with obstruction of the urinary
outflow tract as seen in Western countries arises from an overgrowth of stromal tissue
(fibrous and smooth muscle cells), as well as adenoma cells. Two thirds of plasma
oestrogen is produced by aromatisation of DHEA and androstenedione in the adrenal gland,
while the remaining one third is produced by aromatisation in the testes.
C19-steroids (such as DHEA and androstenedione) are also aromatised peripherally in fat
and muscle tissues. The active form of oestradiol, which is not bound to the sex
hormone binding globulin (SHBG) diffuses into the prostate cells. From mid-life
there is an increase in SHBG and increased peripheral aromatisation of C19-steroids to
produce oestradiol. For both reasons there is a decrease in free active
testosterone. The shift in balance with a relative increase in oestrogens is the
trigger for prostate stromal overgrowth: androgens and oestrogens are synergistic (promote
each others effects) in producing BPH. The Natural History of Prostate CancerWe know more about how it develops than why. We do know that cancer development is a multistage process, commencing with premalignant hyperplastic lesions, and progressing by the initiation and promotion of cancer to an invasive metastatic form with secondaries in bone and elsewhere. The initial site of cancer in the prostate gland has been considered to be peripheral, but we now recognise 25% of tumours arise in the transitional zone where BPH develops, and microscopic BPH is considered a premalignant condition (Bostwick). Tissue removed at surgery for BPH, a prostatectomy, shows diffuse or multifocal proliferation of ductal or epithelial cells, so-called ‘atypical adenomatous hyperplasia’ (AAH), (McNeal 1986). This represents an early phase in the escape of prostate tissue from growth regulatory mechanisms. Prostatic epithelial neoplasia (PIN), in the peripheral zone of the prostate, are also premalignant. Both are age related and occur with greater frequency in the prostate glands of those with cancer than without. ‘Latent carcinoma’ of the prostate is found in 30% of autopsies of men over 50 from all races. 1% of these develop into an invasive cancer during a normal lifetime. Differentiation of cancer cells using a typology that grades malignancy is difficult to support because cells of all types have shown a tendency to be invasive. There are probably multiple factors. Large scale population studies have shown a high fat/low fibre diet, such as is usual in North America and Europe, to be associated with a high incidence of endocrine dependent tumours like cancer of the prostate and breast. Research using retrospective analysis of diets has identified protective effects from certain fruits and vegetables in the development of these cancers (as well as cancer of the stomach and rectum, artherosclerosis, ischaemic heart disease, and liver disease). In particular, protection appears to be given by a group of substances called Flavinoids, examples being b-carotene and lignans (Peto 1981, Hirayamu 1982). Countries in which there is a high fat diet and a high
fruit and vegetable intake, like Finland, have some protective benefit from cancer, while
the low fat and high fruit and vegetable diet of the Japanese confers greater
benefit. Cancer development is greatest where there is a high fat and low fruit and
vegetable intake, as in North America and the UK. Demographic studies in Greece and
Spain have shown high fat intake associated with a low incidence of cardio-vascular
disease and cancer. Unfortunately demographic studies (studies of large populations
of people) show a correlation between disease development and diet, but cannot be used to
prove a causal connection. They are therefore of limited use. As discussed above components of our diet, for example the Flavonoids in fruit and vegetables, give protection against certain forms of cancer. These ‘bioactive’ factors in vegetables, whole grains, fruits and soybean products have precise molecular actions to prevent cancer formation and progression. For instance, breast and prostate cancer growth has been
slowed by increasing dietary lignans and isoflavones. Both are forms of
phyto-oestrogens, that is substances having oestrogenic activity which are derived from
plants.
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