Testosteronsubstitutionstherapie beim Prostatakarzinom

After the fourth decade of life the total testosterone level in men decreases continually. If clinical symptoms, such as decreased libido or erectile dysfunction are combined with a decreased serum testosterone level this is known as late onset hypogonadism (LOH) or partial androgen deficiency in the aging male (PADAM). In such cases testosterone substitution therapy is indicated. One important question is how to treat patients suffering from LOH but also have prostate cancer which was treated curatively in the past? Only relatively little data are available with small numbers of patients which show that testosterone substitution therapy is possible without an increased risk of a relapse in cases of cured prostate cancer. If the patient was cured it does not matter if radical prostatectomy or radiation therapy was used. It is mandatory that patients are well-informed about substitution therapy and that regular surveillance and controls are carried out during the therapy. For patients who still have prostate cancer which has not yet been treated or not yet cured decisions on whether the benefit of the testosterone replacement is greater than the potential risk of a progress of the disease have to be made on an individual case-specific basis.     

Paradigms in androgen/castrate resistant states of prostate cancer in a biomarker era

The last 25 years have witnessed an unprecedented rise in the number of men given a diagnosis of prostate cancer. This has been a major consequence from the clinical application of the biomarker prostate specific antigen (PSA). Importantly, prostate cancer is a malignancy susceptible and adaptative to hormonal changes. Careful understanding of the relation between serum levels of testosterone and PSA is mandatory. Men in whom the prostate has been removed can be considered cured when PSA is no longer detectable and serum testosterone levels are normal. However, this "cured" claim is not possible for those exhibiting castrated levels of testosterone, whether induced or not. The influence of castration in the prognostic paradigm of prostate cancer is transcendental, and serum testosterone levels provide objectivity for proper disease state characterization. Men with metastatic prostate cancer who have not been exposed to hormonal ablation have a different course than men with metastatic lesions resistant to androgen deprivation. These distinctions become complicated when androgen suppression is initiated at earlier states of the disease, or when it is given in response to molecular, not clinical, activity of prostate cancer. Molecular resistance, signaled by rising PSA levels despite castration, in the absence of clinical progression, is a much more common scenario that we must be acquainted with for patient education and proper design of clinical trials.     

Testosteron und Prostata

Testosterone has a distinct role in benign and malignant diseases of the prostate. Therefore, knowledge about the physiological interactions between testosterone and the prostate and the special circumstances under testosterone substitution are of great impact for urologists.PSA value and prostate volume do not show significant changes under testosterone substitution therapy. Even if there are no long-term studies in men under substitution due to decreased testosterone, the therapy seems to be safe under regular control of the prostate with PSA and sonography, and the risk for prostate carcinoma is not increased.In hypogonadal men with high-grade PIN under testosterone substitution, 1 in 20 cases with suspicious rectal examination exhibited a carcinoma; the PSA values did not show a difference between men with or without PIN.Nevertheless, it remains unclear whether men after successful radical prostatectomy should receive testosterone substitution.     

Prostate cancer in Klinefelter syndrome during hormonal replacement therapy

Prostate cancer detection is a rare occurrence in patients with Klinefelter syndrome, in whom chronically low circulating androgen levels are common findings. Administration of exogenous testosterone has increasingly been used to treat young adolescents diagnosed with Klinefelter syndrome and documented androgen deficiency. Although testosterone replacement in adult patients has been associated with prostatic enlargement, it remains unknown whether chronic supplementation of exogenous testosterone to pubescent males with hypogonadism results in early prostate carcinogenesis. We report a first case of prostate cancer in a patient with Klinefelter syndrome who had undergone long-term testosterone replacement therapy since childhood for chronically depressed levels of testosterone.     

Testosterone and the Prostate: The Evidence So Far

It has traditionally been accepted that testosterone substitution in men with testosterone deficiency syndrome has the potential to harm the prostate. This theory originates from 1941 and is based on data presented for only two patients, one of whom had already been castrated. A review of the current peer-reviewed medical literature, however, has proved inconclusive. Whilst there is clear evidence that a reduction in serum testosterone to castration concentrations is able to reduce levels of prostate-specific antigen and delay the progression of established prostate cancer, it is difficult to prove the converse. Recent studies have shown that testosterone replacement has little effect on prostate tissue androgen levels and cellular function, whilst in men with prostate cancer, low serum testosterone levels were reported to be associated with the presence of extraprostatic cancer. Nevertheless, it is clear that the two classical contraindications for the administration of testosterone, that is, suspected or histologically proven prostate cancer and symptomatic benign prostatic hyperplasia, must be carefully respected.     

Review article Testosterone therapy in the ageing male: what about the prostate?

The concerns about testosterone therapy in ageing men with late-onset hypogonadism mainly address the risk of prostatic disease, i.e. either benign prostatic hyperplasia (BPH) or prostate cancer (PCa). Both conditions are highly dependent on androgen action and recent clinical data on the cancer-preventive effect of the 5alpha-reductase inhibitor finasteride have supported the possible role of androgens in PCa. However, the clinical data especially on the long-term effects of exogenous androgen substitution in regard to prostate safety are nonconclusive in many respects. As sufficient clinical studies on these risks will not be available in the near future, the approach of testosterone therapy towards prostate complications should be kept on a safe but practical basis. This review includes some recommendations in regard to testosterone therapy and prostate monitoring in patients with BPH and bladder outlet obstruction, with previous history of curative treatment for PCa or with prostatic intraepithelial neoplasia.     

Determining dosing intervals for luteinizing hormone releasing hormone agonists based on serum testosterone levels: a prospective study

PURPOSE: Long acting luteinizing hormone releasing hormone agonists are the predominant form of androgen suppression in the treatment of prostate cancer with the goal of maintaining castrate levels of testosterone. Current dosing of luteinizing hormone releasing hormone agonists does not include monitoring the end organ response of serum testosterone. Recent evidence suggests standard dosing regimens fail to achieve castrate levels of testosterone in some patients while in other patients testosterone can remain at castrate levels longer than the manufacturer recommended dosing interval. We prospectively evaluated patients with prostate cancer receiving luteinizing hormone releasing hormone agonist hormonal therapy to determine the length of time that serum testosterone remains at or below castrate levels. MATERIALS AND METHODS: A 3-month dose of 22.5 mg leuprolide was administered to all patients as a first dose followed by a second dose 3 months later. Serum testosterone and prostate specific antigen were measured prospectively before starting hormonal therapy, after the first dose (12 weeks) and again following the second dose (24 weeks) to assess if castrate levels of testosterone (50 ng/dl or less) had been reached. At 24 weeks if patient serum testosterone was 50 ng/dl or less, then 22.5 mg leuprolide were not administered, and serum testosterone and prostate specific antigen were checked monthly. When serum testosterone was greater than 50 ng/dl a subsequent dose of 22.5 mg leuprolide was given. Serum testosterone and prostate specific antigen were then checked 3 months later and monthly thereafter until testosterone was greater than 50 ng/dl. Thus, the time that testosterone remained at castrate levels could be accurately established. RESULTS: From February 2003 to August 2005, 42 patients were treated in this manner with a median followup of 18 months (range 10 to 30). Average patient age was 77 years. Median Gleason grade was 7 (range 6 to 9). Median pretreatment prostate specific antigen was 15.1 ng/ml (range 0.6 to 433) and median posttreatment prostate specific antigen was 0.74 (less than 0.1 to 120). The median dosing interval was 6 months (range 5 to 12). Three patients had an increase in prostate specific antigen while receiving treatment despite castrate levels of testosterone. No patient required more frequent dosing than every 5 months. CONCLUSIONS: Testosterone based luteinizing hormone releasing hormone agonist therapy makes empirical sense. It represents continuous androgen ablation based on the patient physiological end point, namely testosterone. Early data suggest that using serum testosterone to guide luteinizing hormone releasing hormone dosing is safe, efficacious and cost-effective. By following end organ response, patients receive individualized care and more accurate androgen suppression therapy.     

The current status of therapy for symptomatic late-onset hypogonadism with transdermal testosterone gel

For over 50 years, testosterone therapy has been used for the treatment of hypogonadism. In recent years, there has been an increase in the use of testosterone therapy for men with late-onset hypogonadism, as more convenient and effective modes of application are developed. Testosterone therapy in these men can significantly improve their sense of well-being, and lead to increases in muscle and bone mass, upper body strength, virility and libido [Gruenewald, Matsumoto. J Am Geriatr Soc 2003;51:101; Morales. Aging Male 2004; in press]. However, ensuring that optimal testosterone therapy is achieved in men with hypogonadism remains challenging. Oral delivery of unmodified testosterone is not possible, due to rapid first-pass metabolism and its short half-life. Therefore, different derivatives and formulations of testosterone have been developed to enhance potency, prolong duration of action or improve bioavailability. In addition, several different routes of administration have now been evaluated, including intramuscular injections, oral formulations, transdermal patches, transbuccal systems and transdermal testosterone gel. Despite the broad range of testosterone therapy on offer, each form has its benefits and limitations, and some will suit one patient more than another. An important concern among clinicians is that testosterone therapy may cause or promote prostate cancer. While current evidence supports the safety of testosterone therapy, androgens are growth factors for pre-existing prostate cancer. Therefore, before therapy is initiated, careful digital rectal examination and determination of prostate-specific antigen (PSA) in serum should be performed, in order to exclude evident or suspected prostate cancer. The first 3-6 months after initiating testosterone therapy is the most critical time for monitoring effects on the prostate. Therefore, it is important to monitor PSA levels every 3 months for the first year of treatment; thereafter, regular monitoring (mostly for prostate safety but also for cardiovascular and haematological safety) during therapy is mandatory.     

Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate

Luteinizing hormone-releasing hormone agonist therapy for prostate cancer is a new method of management for metastatic disease. During the initial 1 to 2-week period of administration an increase in serum testosterone concentration can lead to an exacerbation of clinical symptoms (flare phenomenon). Two patients are summarized who received luteinizing hormone-releasing hormone agonist therapy without flare blockade and died suddenly during month 1 of therapy. A review of 765 patients in 9 series found 10.9% who suffered disease flare and 15 who died during disease flare. Of these 17 patients 12 were similar to our 2. These data suggest that any patient placed on luteinizing hormone-releasing hormone agonist therapy for prostate cancer merits some form of flare blockade during the initial 1 or 2 months of therapy.     

Health related quality of life using serum testosterone as the trigger to re-dose long acting depot luteinizing hormone-releasing hormone agonists in patients with prostate cancer

PURPOSE: Health related quality of life was assessed in patients with prostate cancer on androgen suppression therapy re-dosed based on serum testosterone, and observations were confirmed regarding the safety, efficacy and cost per patient treated with this method of re-dosing luteinizing hormone-releasing hormone agonists. MATERIALS AND METHODS: The study comprised 22 patients with prostate cancer prospectively enrolled in a control-crossover designed trial of dosing depot luteinizing hormone-releasing hormone agonist based on serum testosterone. Health related quality of life using the Expanded Prostate Index Composite and SF-36 instruments was the primary outcome assessed. RESULTS: Median duration of castrate testosterone was 5.5 months (range 3.5 to 10). Longer durations of castrate testosterone significantly correlated with lower pretreatment serum testosterone and smaller body mass index. No significant change from nadir prostate specific antigen was observed during castrate duration. The yearly cost of care was significantly decreased using the method of re-dosing based on serum testosterone ($3,567.90 versus $7,135.80). Short-term overall health related quality of life and patient satisfaction were significantly improved over baseline measurements. However, by study completion overall health related quality of life was equivalent regardless of the dosing method. CONCLUSIONS: Patient assessed health related quality of life improved in the short term and the cost of care decreased with no loss in the quality of care or patient satisfaction using serum testosterone as the trigger to re-dose 10.8 mg. goserelin in patients with prostate cancer on androgen suppression therapy.     

PADAM aus urologischer Sicht

PADAM stands for partial androgen deficiency in the aging male, and it is currently diagnosed with a testosterone level below 3 ng/ml (300 ng/dl or 12 nmol/l), and with symptoms varying according to the individual. The symptoms are a reduction or even loss of libido, a decline in muscle mass and strength, enhancement of visceral fatty tissue-padding, dryness of the skin, apathy, tiredness and distortion of mood right up to depression, and ostalgia due to osteoporosis. Before starting any form of hormonal substitution, which is only indicated if clinical symptoms and testosterone deficiency correlate, it is absolutely essential to exclude prostate cancer by using clinical evaluation and PSA values. Close PSA monitoring is necessary during testosterone substitution. In more than 95% of all patients with erectile dysfunction, the cause is not testosterone deficiency. Even a decreased level of dehydroepiandrosterone (DHEA) in an elderly male needs no replacement. There is also no indication for estradiol therapy in men--except in the rare case of aromatase deficiency.     

Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer

Androgen deprivation therapy (ADT) and 5-α-reductase (5AR) inhibition are used in the treatment of men with advanced or metastatic prostate cancer and benign prostatic hyperplasia (BPH), respectively. These drugs exert their effect by lowering androgen levels in the serum and allegedly, the prostate gland. It is, however, unknown whether (increased) intraprostatic androgen levels are associated with the pathogenesis of BPH and with the initiation and progression of prostate cancer. Also, it is unclear whether intraprostatic dihydrotestosterone (DHT) levels correlate with a response to initial hormonal therapy or with patient outcome. These uncertainties have resulted from the finding that serum testosterone levels do not necessarily reflect those in the prostate gland. Intraprostatic DHT levels of men being treated with 5AR inhibition, of those treated with ADT for hormone-naive prostate cancer, and of those with castration-resistant prostate cancer are all altered in an equivalent manner because of hormonal manipulation. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels, may lead to treatment that is tailored to the needs of the individual patient, and probably to new therapeutic targets as well.     

Prostate cancer in men using testosterone supplementation

PURPOSE: Although an association between testosterone supplementation and the development of prostate cancer is unproven, a recent increase in the use of this therapy has reopened the debate about its safety in men at risk for prostate cancer. To increase awareness of this risk, we report on a series of patients in whom clinically significant prostate cancer developed and was presumed to be related to exogenous testosterone use. MATERIALS AND METHODS: The medical records of 6 urology practices were reviewed to identify men undergoing testosterone supplementation for sexual dysfunction or "rejuvenation " who were found to have prostate cancer after initiation of exogenous testosterone supplementation. Cases were analyzed to determine clinical and pathological parameters characterizing the presentation of prostate cancer. RESULTS: A total of 20 men were diagnosed with prostate cancer after initiation of testosterone therapy. Prostate cancer was detected within 2 years of testosterone initiation in 11 men (55%) and from 28 months to 8 years in the remainder. The tumors were of moderate and high grade, being Gleason sum 6, 7 and 8 to 10 in 9 (45%), 6 (30%) and 5 (25%) men, respectively. Median serum prostate specific antigen (PSA) concentration at diagnosis tended to be low at 5.1 ng/ml (range 1.1 to 329.0) and digital rectal examination generally proved more sensitive than PSA assays in detecting the cancer. Patients seen by nonurologist physicians were monitored less often for prostate cancer during testosterone use than those followed by urologists. CONCLUSIONS: Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment. Digital rectal examination is particularly important in the detection of these cancers. Physicians prescribing testosterone supplementation and patients receiving it should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.     

A rational approach to androgen therapy for hypogonadal men with prostate cancer

With earlier detection and improved survival from early stage prostate cancer, it is likely that the numbers of men presenting with hypogonadal symptoms following curative surgery for their cancer will increase. Although testosterone supplementation is effective in improving symptoms of hypogonadism, traditionally such therapy has been contraindicated in patients who have had prostate cancer. This paper reviews the evidence that testosterone therapy can be safely given to selected men with hypogonadism who have had prostate cancer but currently have no evidence of disease by clinical and prostate-specific antigen (PSA) criteria. Such patients should be treated cautiously and followed closely.     

Early chemotherapy in prostate cancer

A considerable proportion of men with clinically localized prostate cancer are not cured by surgery or radiotherapy, and hormone therapy for advanced disease is also not curative. Given the demonstrable efficacy of chemotherapy in hormone-refractory disease, there is an interest in examining the curative potential of chemotherapy when administered early in the natural history of prostate cancer. It is hoped that chemotherapy could be used with hormone therapy and in the adjuvant setting, as is the case in many other solid tumors, in patients with 'high-risk' prostate cancer who are undergoing primary radical prostatectomy or radiotherapy. Early phase clinical trials have shown that using docetaxel as neoadjuvant or adjuvant therapy is safe and feasible. In the neoadjuvant setting, tumor shrinkage, serological response, there is some evidence of pathological downstaging. Several randomized trials are ongoing, and it is anticipated that the results of these studies will help to identify whether the early use of chemotherapy in early prostate cancer is beneficial.     

Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review

This paper provides a systematic review of the literature about prostate cancer risk associated with testosterone therapy for hypogonadism. A comprehensive search of MEDLINE, EMBASE and other resources was conducted to identify articles that highlight occurrences of prostate cancer in men receiving testosterone therapy for hypogonadism treatment. Articles that met study inclusion criteria were assessed for causality between testosterone treatment and prostate cancer, increased prostate-specific antigen or abnormal digital rectal examination findings. Of 197 articles relating to testosterone therapy, 44 met inclusion criteria: 11 placebo-controlled, randomized studies; 29 non-placebo-controlled studies of men with no prostate cancer history; and 4 studies of hypogonadal men with history of prostate cancer. Of studies that met inclusion criteria, none demonstrated that testosterone therapy for hypogonadism increased prostate cancer risk or increased Gleason grade of cancer detected in treated vs untreated men. Testosterone therapy did not have a consistent effect on prostate-specific antigen levels.     

Prostate tissue androgens: history and current clinical relevance

Direct determination of androgen levels in prostate tissue provides a perspective on the organ that is not available via androgen serum levels. The principle prostatic androgens, primarily dihydrotestosterone (DHT) and secondarily testosterone, can be readily assayed in quick-frozen prostate biopsy cores or surgical specimens. Such assays have proved important in establishing (1) that DHT is a permissive factor in BPH pathogenesis, (2) a mechanism for the treatment of BPH, (3) an understanding of prostate cancer chemoprevention, (4) an explanation for the 'escape' of prostate cancer from castration therapy, (5) prostate safety of testosterone replacement therapy, and (6) insights into the cause of racial differences of prostate cancer. Future opportunities include clarification of new drug mechanisms for BPH and prostate cancer, as well as a better understanding of the pathogenesis of both, and as an aid in individual patient management. Determination of prostate tissue androgens may soon transition from research tool to clinical test.     

Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men

PURPOSE: We documented the experience of 2 urology practices with the use of testosterone supplementation to treat hypogonadal men who had undergone curative radical prostatectomy for localized prostate cancer. We also reviewed the literature for reports of the use of testosterone in men surgically cured of prostate cancer. MATERIALS AND METHODS: A retrospective review of clinical records of 2 busy private urology practices was used to compile brief case histories of hypogonadal men treated with testosterone who had undergone curative radical prostatectomy for localized prostate cancer. Using MEDLINE and BIOSIS Previews (Biological Abstracts, Inc., Philadelphia, Pennsylvania), the literature was searched for articles describing the use of testosterone in men surgically cured of organ confined prostate cancer. RESULTS: The case records of 7 hypogonadal men who had undergone curative radical prostatectomy were identified. All men had clinical symptoms of hypogonadism and low serum testosterone levels. Each man was treated with an androgen preparation. After variable followup periods no biochemical or clinical evidence of cancer recurrence was found in any of the group. No reports in the literature were found of a similar therapeutic approach for such patients. CONCLUSIONS: Based on the clinical experience with this small group of men, and indirect evidence of the safety of this approach from epidemiological and clinical data, further cautious use of testosterone in a carefully selected population seems warranted.     

Is low serum free testosterone a marker for high grade prostate cancer?

PURPOSE: The association of free and total testosterone with prostate cancer is incompletely understood. We investigated the relationship of serum free and total testosterone to the clinical and pathological characteristics of prostate cancer. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 117 consecutive patients treated by 1 physician and diagnosed with prostate cancer at our medical center between 1994 and 1997. Low free and total testosterone levels were defined as 1.5 or less and 300 ng./dl., respectively. RESULTS: After evaluating all 117 patients we noted no correlation of free and total testosterone with prostate specific antigen, patient age, prostatic volume, percent of positive biopsies, biopsy Gleason score or clinical stage. However, in patients with low versus normal free testosterone there were an increased mean percent of biopsies that showed cancer (43% versus 22%, p = 0.013) and an increased incidence of a biopsy Gleason score of 8 or greater (7 of 64 versus 0 of 48, p = 0.025). Of the 117 patients 57 underwent radical retropubic prostatectomy. In those with low versus normal free testosterone an increased mean percent of biopsies demonstrated cancer (47% versus 28%, p = 0.018). Pathological evaluation revealed stage pT2ab, pT2c, pT3 and pT4 disease, respectively, in 31%, 64%, 8% and 0% of patients with low and in 40%, 40.6%, 12.5% and 6.2% in those with normal free testosterone (p>0.05). CONCLUSIONS: In our study patients with prostate cancer and low free testosterone had more extensive disease. In addition, all men with a biopsy Gleason score of 8 or greater had low serum free testosterone. This finding suggests that low serum free testosterone may be a marker for more aggressive disease.     

A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy

PURPOSE: Patients with prostate cancer are treated with neoadjuvant, adjuvant and intermittent androgen deprivation therapy. Prostate specific antigen (PSA) is altered during androgen deprivation therapy, and as a result the prognostic significance and accuracy of PSA values measured before serum testosterone has normalized are questionable because the patient is still effectively on androgen deprivation therapy. We determine the time it takes for serum testosterone to return to normal after withdrawal of androgen deprivation therapy. MATERIALS AND METHODS: Serial serum testosterone was prospectively measured at 3-month intervals in 68 men after withdrawal of androgen deprivation therapy. The number of months to return to normal serum testosterone 270 ng./dl. or greater, was calculated for each patient. Patients were stratified according to duration of androgen deprivation, age and type of luteinizing hormone releasing hormone agonist used. RESULTS: Median patient age was 71 years (range 46 to 88). Median time to normalization of testosterone was 7 months (range 1 to 58). At 3, 6 and 12 months 28%, 48% and 74% of men had normal serum testosterone, respectively. Serum testosterone took significantly longer to return to normal in patients on androgen deprivation therapy for 24 months or greater compared to those on therapy for less than 24 months (log-rank p = 0.0034). There was no statistical significance based on age or type of luteinizing hormone releasing hormone agonist used. CONCLUSIONS: Androgen deprivation has an effect on serum testosterone that extends beyond the cessation of treatment. Serum testosterone should be measured in all men until normalization. These results should be applied to the interpretation of PSA levels after withdrawal of androgen deprivation therapy. In addition, these data have implications regarding dose scheduling and definition of biochemical (PSA) failure after primary therapy.