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Prostate disease and the pharmaceutical industry
Prostate Cancer
Medicines that stop testosterone production
Research in the pharmaceutical industry and elsewhere showed
that a LHRH agonist given in pulses by injection mimics the
natural action of LHRH itself and induces the release of LH
from the pituitary gland. An unexpected finding, however,
was that if a LHRH agonist was given continuously, the pituitary
was first stimulated, but after some days ceased to respond.
During the period of initial stimulation, more LH is released
and consequently there is a surge in testosterone from the
testes. After a few days, the pituitary becomes desensitised
by the continuous presence of the hormone, loses its membrane
receptors for LHRH and hence stops releasing LH. When that
happens, the testis stops making testosterone. Thus, LHRH
agonists could help in prostate cancer by switching off the
testosterone necessary for the cancer to grow.
But why not give LHRH itself? This is mainly because it only
survives in the body for a short time. So the search began
for related but more stable molecules. The result was the
discovery of potent ‘super-agonists’ and methods for making
them more available in the body. Four are now available in
the UK – buserelin (Shire), goserelin (AstraZeneca), leuprorelin
(Wyeth), and triptorelin (Ipsen). At the start of treatment,
all four compounds cause a rise in testosterone, called a
‘flare’, and during this time, about one in ten men with metastatic
cancer may experience a temporary worsening of their symptoms.
After that, the testosterone declines to levels that would
be seen in surgical castration and the tumour ceases to grow.
In fact, castration is an option in metastatic cancer, but
in many men the loss of the testicles is psychologically distressing:
Given the choice, most would choose ‘medical castration’ involving
the use of an LHRH agonist, which is reversible if it is discontinued.
To overcome the instability of these medicines, special
formulations have been developed. One exploits the discovery
that LHRH agonists are absorbed through the membranes of the
nose. This has been exploited in buserelin, which has been
developed as an intranasal spray. For eight days, the patient
is given injections, but from then on the nasal spray can
be used. Different technology has been employed with goserelin,
leuprorelin and triptorelin. Here, the active medicine is
trapped in minute microspheres which can be injected into
the muscle or under the skin, where they slowly break down,
releasing the medicine steadily and continuously. Further
injections are given at monthly intervals, and in the case
of goserelin and leuprorelin, three-monthly forms are also
available. The polymer used to make the microspheres is similar
to that used for medical stitches and is entirely safe.
A somewhat different medicine is fosfesterol tetrasodium
(Asta Medica). This is an inert substance related to the female
hormone, oestrogen. Once inside the human body, it is converted
by enzymes within the tumour into diethylstilbestrol, which
in turn acts to reduce testosterone levels. The compound can
be used at all stages of prostate cancer, but is mostly employed
in people undergoing surgery, in inoperable cases, or to reduce
bone pain.
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