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Introduction
At present prostate cancer is the second cause of death due to cancer in European men and hence an important health problem in many countries [1]. Because of the increased publicity on prostate cancer and the fact that there is a blood test available to indicate its presence (prostate specific antigen; PSA), prostate cancer is nowadays more often diagnosed at an early stage. In the past a locally advanced or metastatic tumor has been found in approximately 70% of all newly diagnosed patients, this has decreased to 30% in the most recent years. When prostate cancer is diagnosed at an early stage, the first choice is a curative treatment by surgery or radiotherapy, provided the patient has a good life expectancy. The problem, however, is that in this group of patients a biochemical recurrence (only a PSA elevation, without objective signs or symptoms of progression) will be found in 30% at a certain time during follow-up. At this moment it is not yet clear which therapy is the best for this group of patients (early versus delayed hormonal treatment), as far as survival and the influence on the quality of life are considered [2]. Androgen deprivation is still the therapy of choice for patients with metastatic prostate cancer. This therapy induces symptom reduction and biochemical response in 80 to 90% of the patients with symptoms due to local invasion or metastases. Sometimes there is also an objective response. Nevertheless, androgen deprivation should be considered as palliative treatment. In most cases subjective or objective recurrence is seen after 1,5-2 years, with a subsequent overall survival of 18 months [3]. Therefore, the quality of life is an important aspect and the side effects of hormonal therapy should be balanced against the possible survival benefit or palliation.
In symptomatic metastatic prostate cancer, hormonal therapy provides a good palliative effect and patients will therefore accept the side effects of the hormonal therapy. Recently, a combination of radiotherapy plus three years of androgen deprivation showed to increase survival in patients with non-metastatic prostate cancer but a high risk tumor (G3=poorly differentiated, T3-T4) compared to external beam radiotherapy alone [4].
In the next paragraphs different forms of androgen deprivation and the mechanisms of action will be described. Furthermore the side effects and their possible treatment will be reviewed.
Hormonal dependency of prostate cancer
The influence of androgens is probably one of the most important factors for malignant transformation of prostate tissue and further growth. The testes are responsible for 90-95% of circulating testosterone levels; the remainder is secreted by the adrenal glands. The testes and adrenal glands are influenced by the hypothalamus and the anterior pituitary gland. In the prostate testosterone is converted into dihydrotestosteron (DHT) by the enzyme 5-alpha-reductase. DHT is the primary androgen that stimulates growth of benign and malignant prostate tissue. Huggins and Hodges showed for the first time that growth of prostate cancer can be inhibited by hormonal manipulation (orchidectomy). With this observation the hormonal dependency of prostate cancer was shown [5]. Initially, surgical castration was the only possible treatment for prostate cancer. New treatments were introduced after the discovery of new molecules that intervened on different levels in the hypothalamic-pituitary-testicular axis.
Surgical castration
During surgical castration both testes are removed through a scrotal midline incision, resulting in an immediate decrease of the testosterone level. Subcapsular orchidectomy was described after some years, with similar effects on testosterone levels. The main advantage is a possible psychological effect while more residual tissue remains in the scrotum, but this psychological effect has never been substantiated.
The advantage of surgical castration is a rapid palliative effect. Bone pains can sometimes dissolve the same day in a patient with painful bone metastases.
The side effects of a subcapsular orchidectomy can be related to the operation itself (infection, bleeding, and pain) and to the effects of the hormonal manipulation. Approximately 90% of patients have erectile disturbances due to a low testosterone level. Hot flushes also are a common side effect and can be very troublesome if the patient has to change clothes many times a day due to excessive sweating. Hot flushes are caused by elevated central norepinephrine levels (there is no inhibition of LH-production) stimulating the central heat centre [6]. The treatment of these ‘hot flushes’ is based on inhibition of these elevated central norepinephrine levels. This can be achieved by a steroidal antiandrogen (cyproterone acetate), which has both a gestagenic and antiandrogenic effect [6]. Other methods are the addition of megestrol acetate or a selective serotonine ‘uptake’ inhibitor as venlafaxine [7]. On the long-term an increase of weight is often seen. Initially prognosis in patients with metastatic prostate cancer was poor, because patients were diagnosed in a (too) late stage. With patients being exposed to a low testosterone level for a long time, long-term side effects are more frequently seen. The most important of these are psychological changes (‘does not feel as a man’), anaemia, loss of muscle and osteoporosis, resulting in spontaneous, not tumor related fractures. The decrease of bone density starts relatively early in men with castration levels of testosterone. Bone density loss has been demonstrated after 6 to 9 months of androgen deprivation [8]. Bone density can be measured by ‘Dual-energy X-ray absorptiometry’ (DEXA) -scans. To prevent this complication some support the combination of castration with bisphosphonates [9]. The optimal moment for the addition of bisphosphonates is not clear yet. Daily supplements of 500 mg calcium and 400 IU vitamin D and sufficient physical exercise, however, is recommended in men starting androgen suppression for prostate cancer.
LHRH-analogues
‘Luteinizing-hormone releasing-hormone’ (LHRH) is produced in the hypothalamus and stimulates the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the pituitary gland. When synthetic LHRH-analogues became available they were tested in the treatment of patients with prostate cancer.
Initially a transient elevation of the testosterone level develops with this treatment modality which can also stimulate the prostate cancer cells to proliferate. This can lead to deterioration of symptoms (‘flare-up’ phenomena). Patients with a metastasis in the spinal column can develop a paraplegia or an obstruction of the upper urinary tracts. This LHRH monotherapy is therefore contraindicated in patients with symptomatic (painful osseous metastases) prostate cancer. The initial rise of testosterone level disappears after 7-14 days, because continuous high dose of a synthetic LHRH analogue results in down regulation of LHRH-receptors. This results in a low LHRH-level, causing castration levels of testosterone (chemical castration).
Both short- and long-term side effects of chemical castration are similar to surgical castration. The LHRH-analogues can be administered subcutaneously or intramuscular in daily, monthly, and 3-monthly and (as recently demonstrated) yearly formulations.
The advantage of chemical castration is the reversibility of this treatment modality. Besides, psychological advantages are demonstrated, because the testes remain in situ. Although recently Potosky et al reported that patients on LHRH therapy reported more physical discomfort and worry because of cancer or its treatment than did orchiectomy patients. LHRH patients assessed their overall health as fair or poor more frequently than did orchiectomy patients and also were less likely to consider themselves free of prostate cancer after treatment [10]. Complications of the treatment with an LHRH-analogue are minimal, sometimes small bleedings at the injection site occur, hypersensitivity is rare. It is important to check if the patient reaches castration levels of testosterone, especially if there is no PSA response. In certain cases proper chemical castration cannot be achieved. Then it will be necessary to perform a surgical castration.
LHRH-antagonists
Synthetic LHRH-antagonists have a unique aminoacid substitution, by which they have a pure LHRH-antagonistic capacity by competitive LHRH-receptor blockade. LHRH-antagonists do not induce an initial stimulation of gonadotrophin release like LHRH-analogues do, but cause an almost immediate and reversible suppression of gonadotrophin secretion. By this antagonist action a ‘flare up’, as seen with LHRH-analogues is prevented. In most patients testosterone castration levels are achieved after approximately 14 days. A LHRH-antagonist like AbarelixŽ used as monotherapy induces a faster chemical castration in comparison with maximal androgen blockade (LHRH-analogue or surgical castration in combination with an anti-androgen) [11]. The side effects of LHRH-antagonists do not differ from those induced by LHRH-analogues, although allergic reactions have been described due to histamine release. For this reason the ‘Food and Drug Administration’ in the United States has registered this drug only for patients with metastatic prostate cancer and for those without treatment alternative. It remains to be seen whether other advantages from these LHRH-antagonists will be demonstrated.
Estrogen therapy
Estrogens influence the growth of prostate cancer by a negative feedback on the hypothalamic-pituitary axis. High serum concentrations of estrogens reduce the secretion of LHRH from the hypothalamus, which in turn reduces LH release from the pituitary gland. This stops the production of testosterone in the Leydig cells in the testes. Furthermore, high doses of estrogens can occupy the androgen receptor which can lead to a direct cytotoxic effect on androgen sensitive and androgen insensitive prostate cancer cells [12]. Most studies that report the influence of estrogens in prostate cancer have used diethylstilboestrol (DES) in a 1-5 mg dose. DES was as effective as orchidectomy, but there was also an evident increase in cardiovascular side effects induced by the estrogens, especially with higher doses (3 and 5 mg).
When taken orally estrogens bypass the liver. Exposition to the portal circulation changes the metabolism of hormones, coagulation proteins and lipids. Disturbance of the physiological composition of orally administered estrogens elevates the risk of cardiovascular side effects. In the last two decades oral administration has rarely been used, although it is a very cheap treatment. In order to prevent cardiovascular side effects, treatment can be combined with aspirin (although few case series have been published) or estrogens can be administered parenterally. The ‘Scandinavian Prostatic Cancer Group’ has shown that this form of administration does not induce an elevated cardiovascular risk, because the estrogens do not pass the liver [13].
Recently a study has been published that describes transdermal estrogen therapy, with an even lower risk on cardiovascular toxicity, compared to the oral administration of estrogens [14].
Besides the aforementioned serious cardiovascular side effects of DES-therapy, gynecomastia is also frequently seen. In some cases radiotherapy or tamoxifen therapy is applied on the breasts. The influence of estrogens on bone density is not very clear, but possibly estrogens have a protecting effect [15,16]. Another interesting finding in relation to the estrogens is the beneficial effect on cognitive function [17].
Anti-androgens
There are two groups of anti-androgens, the steroidal (cyproterone acetate and medroxyprogesterone acetate) and the non-steroidal (flutamide, nilutamide and bicalutamide). Anti-androgens bind to the androgen receptor in the prostate and antagonize testosterone and dihydrotestosterone (DHT). This is the only action of the non-steroidal anti-androgens. Hence, LH levels do not decline and serum testosterone levels remain the same or even increase. With this treatment libido and erectile function will theoretically not be impaired and there is no risk of osteoporosis.
Compared to the non-steroidal anti-androgens, steroidal anti-androgens also have a gestagenic effect, with a central effect on the pituitary gland resulting in decreased LH levels. This means that libido and erectile function will theoretically be affected. Treatment with non-steroidal anti-androgens frequently causes gynecomastia or painful nipples. This side effect is caused by the peripheral aromatization of circulating androgens in estrogens. 18 In most cases prophylactic radiotherapy of the breasts is advised (6-12 Gray in 1 dose or divided in 3 days), before commencement of non-steroidal anti-androgen therapy. Sometimes this does not have a definite effect. Positive effects of TamoxifenŽ, an estrogen antagonist, have been reported in treatment of gynecomastia. Aromatase inhibitors like testolactone could prevent peripheral aromatization of androgens. However, the consequences of both treatment options and their influence on the hypothalamic-pituitary-testicular axis are not known. Other side effects of anti-androgens are gastrointestinal complaints like diarrhoea, liver function disturbances (flutamide), impaired light-dark adaptation, pneumonitis and alcohol intolerance (nilutamide).
Conclusion
Androgen deprivation therapy is an important aspect in the treatment of patients with prostate cancer. Before, men were mostly diagnosed at a later stage, with metastases already present. In that case the role of hormonal therapy is clear. Nowadays, treatment options have increased due to an increased awareness and active screening or early detection programs. A situation that is now frequently encountered is a patient with locally advanced prostate cancer or biochemical progression (elevated PSA) following treatment with curative intent. There is now evidence that the combination treatment of hormonal therapy with external beam radiotherapy results in an increased survival compared to radiotherapy alone. But it is not known for how long this androgen deprivation treatment should be continued. It is to be expected that patients, who receive androgen deprivation for three years, have only a slight chance on recovery of the erectile function. It is not known what the influence is on bone density after the cessation of anti-androgen therapy. Whether anti-androgen monotherapy is sufficient after external beam therapy for locally advanced prostate cancer is also unclear.
Patients with a biochemical progression after radical prostatectomy have a life expectancy of approximately 13 years [19]. When a patient will be exposed to androgen deprivation for such a long time, it is to be expected that this will influence the quality of life significantly. Adjustment of androgen deprivation should be considered and new treatment modalities for this group of patients will have to be developed. The quality of life should be considered in relation to the possible benefit of survival especially in this good prognosis group.
Recommendations for clinical urological practice
1. In patients with locally advanced prostate cancer combination treatment of hormonal therapy and external beam radiotherapy gives a better survival than external beam radiotherapy alone. It is unclear for how long hormonal therapy should be given.
2. In case of biochemical progression after curative treatment there are indications that after radical prostatectomy the patient has still a life expectancy of approximately 13 years.
3. For prostate cancer with metastases hormonal therapy is the treatment of choice. Dependent on the extent and symptoms anti-androgen monotherapy or chemical/surgical castration can be chosen. The advantages and disadvantages and side effects of this therapy should be discussed with the patient

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Th. M. de Reijke
Academic Medical Centre
Department of Urology
Meibergdreef 9
1105 AZ Amsterdam
tel. (0031) 20 5666 60 04
t.m.dereyke@amc.uva.nl