The hormonodependence of certain tumours has for a long time been demonstrated.
It is known, for example, since the end of nineteenth century, that bilateral ovariectomy improves breast cancer.
In 1941, Higgins demonstrated that bilateral castration considerably improved metastatic bone pain in prostate cancer sufferers. It is has also been acknowledged for many years that castrated men never develop prostate carcinoma.
Def: Hormonal therapy is one of the major modalities of medical treatment for cancer, others being cytotoxic chemotherapy and targeted therapy (biotherapeutics). It involves the manipulation of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or drugs which inhibit the production or activity of such hormones (hormone antagonists). Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing, or even undergo cell death. Surgical removal of endocrine organs, such as orchiectomy and oophorectomy can also be employed as a form of hormonal therapy.
In practice, we can study the following cancers as hormonodependent:
breast cancer,
prostate cancer,
corpus uteri cancer,
thyroid cancer,
for few and short responses: ovarian and kidney cancers.
content:
Protein receptors to hormones
Role of castration
Role of steroid hormone
Role of analogues of hypothalamic hormones ( LH-RH)
Estrogens and anti-estrogens
Androgens and anti-androgens
Progesterone
Anti-aromatase
Adjuvant Hormonotherapy
Hormonal treatment of metastases
Thyroid Hormonotherapy
Steroid hormones (from vitamin D to suprarenal hormones) act by their fixation to a specific receptor situated inside the cell nucleus. The complex is a DNA transcription factor which induces various protein syntheses. Steroid receptors are proteins from 427 to 984 amino acids with many analogical zones from one species to another and from one receptor type to another.
General diagram of the action of steroid hormones on hormone sensitive cancer cells
The steroids, linked to more or less specific serum proteins, freely penetrate into the cancer cells and are then transported towards the nucleus by a specific cytosol receptor. The receptor itself is bound to the heat shock protein.
When in the nucleus, the receptor activates the transcription of the synthesis necessary for good cell trophicity.
Receptors are active in several domains:
Specific hormone recognition domain,
DNA Binding domain
Assay methods for receptors
Two techniques are used:
Either isotope techniques, using a tracing dose of radioactive hormone, which tests the nuclear extracts
Or immunochemical techniques which can be applied on tissue extracts or directly on histological preparations.
In clinical practice, oestrogen and progesterone receptors are tested in breast cancer specimens. There is an excellent correlation between the presence of oestrogen receptors in tumour tissue and the response to hormonal therapy.
Relationship between the presence of receptors and survival in breast cancer.
Progesterone receptors are synthesised after the action of oestrogens and thus reflect the actions of both oestrogens and progesterone on tumour cells.
The presence of receptors is a good prognostic factor: breast cancer patients with positive receptors have a longer survival without relapse than patients without detectable receptors.
There has been less study on receptors for prostate cancer. The conversion of testosterone by the prostate cell via a 5- α reductase, enables the reduced hormonal molecule to penetrate into the nucleus.
Hormonal therapy is based on the possibilities of breaking the interaction between testosterone or its derivative with its receptors, thus reducing the transcription factors induced by the combination of the hormone and its receptor.
Mechanisms of action :
The mechanisms of action of the various hormonal treatments correspond to one of the following:
Disappearance of the stimulating hormone,
Action of an antihormone acting of the receptor,
Inhibition of the synthesis of the stimulating hormone or of its active derivate.
The three main mechanisms of hormonal action for prostate cancer:
Disappearance of the stimulating hormone (physical or chemical castration),
Inhibition of the synthesis of the active derivative (5-dehydrotestosterone),
Action of an antihormone on the receptor.
For breast carcinoma, the 5-a reductase is replaced by the action of anti-aromatase, with a relatively similar effect (inhibition of synthesis).
The following pages describe the actions of the various products (or techniques) used in daily clinical practice.
Castration :
In breast carcinoma
Physical castration is generally delivered by radiotherapy or more rarely by coelioscopy. Nowadays, it is performed to a lesser extent in breast carcinoma, mainly due to the simplicity of use of antioestrogen drugs.
However, it still constitutes an excellent treatment modality for breast cancer bone metastases (if no previous treatment with antioestrogens has been administered): a very powerful and rapid analgesic effect is generally obtained with tumour regression and often prolonged survival.
There are major side effects among young non-menopaused women, due to the abrupt menopause induced by castration and its often severe psychological consequences.
In prostate cancer
In prostate cancer, castration has a very strong positive effect on local relapse (disappearance of most urinating difficulties) as well as distant bone metastases (very early pains sedation).
Adding castration to local treatment does not appear to be of any value (despite a recent trial demonstrating benefit with an association of radiotherapy and hormonal therapy for large T3 prostate cancer).
Castration of men is a very simple surgical procedure which can be performed with virtually no hospitalisation and without any major surgical risk. Its cost is very low compared to other treatments proposed further on.
Many of side effects of castration are similar in male and female patients alike. The sudden hormonal deprivation leads to very severe hot flushes, more or less severe hypogonadism (small penis, disappearance of male body hair, softening of the skin, as well as frequent loss of libido with more or less complete impotence (which may already exist in prostate cancer).
There are also many psychological effects: many patients consider castration as an attack on their integrity (many physicians are reluctant to propose such ‘mutilation’ and prefer ‘chemical castration’ which, during the first months at least, appears less aggressive.
Pulpectomy is another possible method, consisting in the removal of the testicular parenchyma whilst conserving the testicular capsule, thus giving a false impression of organ conservation. Some surgeons also suggest replacing testes by prostheses.
Steroid hormones :
In breast carcinoma
Androgens were previously used for treating metastatic breast carcinoma.
They induce a castration effect by blocking hypothalamus hormones.
The virilisation observed in long_term treatment, together with the risks of hypertension and the appearance of new drugs, far better tolerated by patients, have led to the disappearance of androgens from the therapeutical repertoire, except (perhaps) in pre-terminal phases when their anabolising effect can be useful (improved appetite, lesser asthenia).
In prostate cancer
Oestrogens were, for a long time, used to treat prostate cancer.
The most frequently used drugs were diethylstilbestrol as well as estradiol di-undecylate (or Oestradiol –Depot ).
They have peripheral side effects which are symptoms of feminisation: gynaecomastia, altered repartition of fatty tissue), however their main action consists in blocking the secretion of the hypothalamus hormone LH RH, thus inducing a suppression of LH by the pituitary gland and secondarily of testosterone by the testis.
Oestrogens (especially at high prolonged dosages 3mg/d) have been abandoned because of the thrombosis and embolism complications that they induce and which diminish the positive effect of the treatment in randomised studies. Unfortunately, a dosage of 1 mg/d may not be sufficient for all patients. Thus, (at least in France), oestrogens are no longer a first-line hormonal treatment for prostate cancer.
Following the failure of first-line hormonal treatment, DES may offer significant responses.
Oestrogens can also be used in a loading dose (for acute complications which are not amenable to surgery or radiotherapy, such as diffuse medullar compression or very intense pain).
Fosfetrol (or ST 52) is a prodrug which brings the active agent to the prostate. Dephosphorylation induces the formation of the active metabolite: diethylstilbestrol (DES). Due to the presence of acid phosphatases, Fosfetrol is mainly (but not solely) transformed at the tumour site, which avoids general oestrogen treatment and a much higher dosage to the prostate, thus limiting the risk of gynaecomastia, thrombosis and pulmonary embolism.
Moreover, as for oestrogens, the inhibition of the hypothalamus-pituitary axis is observed, thus reducing the testicular synthesis of androgens.
Agonists of LH-RH :
The synthesis of numerous LHRH analogues and the production of easy to use galenic forms (injections with depot properties) has transformed the hormonotherapy of prostate cancer (and to a lesser extent breast cancer)
These drugs have many non-cancer-related indications (endometriosis, uterine fibroma, ovarian polycystosis, hirsutism).
The main drugs are:
buserelin,
goserelin,
leuprorelin,
triptorelin.
The mechanism of action of these LHRH agonists is explained by the down-regulation in the pituitary gland: pituitary receptors for LHRH are totally saturated and then down-regulated with loss of sensitivity to any further stimuli. The gonad receptors for LH and FSH are then reduced. High dosage of LHRH agonists induces inhibition of pituitary and gonad functions (sex steroid deprivation).
The pituitary cells, will initially respond to the stimulation of hypothalamic hormone analogues by increased LHRH secretion. The testis will respond to this secretion by increased testosterone synthesis.