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Lower Testosterone Levels With Luteinizing Hormone-Releasing Hormone Agonist Therapy Than With Surgical Castration: New Insights Attained by Mass Spectrometry
Abstract
Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level which is currently defined as less than 50 ng/dl. The results of previous studies are based on testosterone immunoassays that have insufficient accuracy in the low range. In this study we reevaluated serum testosterone concentrations in men on androgen deprivation therapy using isotope dilution-liquid chromatography-tandem mass spectrometry, an accurate method of measuring testosterone in the castrate range.
Subjects underwent surgical castration (34) or received a luteinizing hormone-releasing hormone agonist (32). Serum samples were obtained more than 3 months after surgery or initiation of luteinizing hormone-releasing hormone agonist therapy. Testosterone levels were determined using isotope dilution-liquid chromatography-tandem mass spectrometry. Dihydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and inhibin B levels were determined.
All subjects had serum testosterone values less than 50 ng/dl and 97% had testosterone concentrations less than 20 ng/dl. Medically castrated men had significantly lower testosterone levels (median 4.0 ng/dl, range less than 2.9 to 20.2) than those surgically castrated (median 9.2 ng/dl, range less than 2.9 to 28.8, p <0.001). No difference was found in dehydroepiandrosterone sulfate, androstenedione and sex hormone-binding globulin levels between the groups, whereas inhibin B levels were significantly higher in the luteinizing hormone-releasing hormone agonist treated group.
Using an accurate technique for testosterone measurement, subjects on luteinizing hormone-releasing hormone agonist therapy had significantly lower testosterone concentrations than men who underwent surgical castration. The clinical relevance of these findings remains to be determined.
... Because CPA acts as an androgen receptor antagonist with progestogenic and glucocorticoid activity (11), some studies suggest it also induces changes in other androgen concentrations such as androstenedione (A4), dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS), but findings are inconsistent (12,13). After gonadectomy, anti-androgens are stopped, and androgen profiles may change once more because androgen production also takes place in the adrenals and at peripheral sites (14). In our clinical experience, some transgender women report increased bodily hair growth after gonadectomy when CPA therapy is stopped. ...
... We did not replicate findings from an earlier study by van der Sluis et al in a mixed cohort of adult transgender women and cisgender men who underwent surgical or hormonal castration because of prostate cancer. They reported lower TT in subjects using an LH-releasing hormone agonist compared with after gonadectomy (14). This discrepancy may be explained by the smaller sample size (66 subjects), the use of different androgenreducing medication, differential effects on SHBG, or the heterogeneity of the sample. ...
... Although all forms of ADT aim to suppress T to castration levels, there has been disparity regarding the target. Recent advancements in assay technologies have enabled quantification of T levels down to extremely low levels (e.g., 2 ng/dL) [78,79] and helped establish that T levels in surgically castrated men are substantially lower than originally reported [7,78]. Based on these results, the European Association of Urology (EAU) updated its PCa guidelines in 2014 to define the target for T during ADT as <20 ng/dL [80]. ...
... Although all forms of ADT aim to suppress T to castration levels, there has been disparity regarding the target. Recent advancements in assay technologies have enabled quantification of T levels down to extremely low levels (e.g., 2 ng/dL) [78,79] and helped establish that T levels in surgically castrated men are substantially lower than originally reported [7,78]. Based on these results, the European Association of Urology (EAU) updated its PCa guidelines in 2014 to define the target for T during ADT as <20 ng/dL [80]. ...
Background:
Androgen deprivation therapy (ADT) is foundational in the management of advanced prostate cancer (PCa) and has benefitted from a recent explosion in scientific advances. These include approval of new therapies that suppress testosterone (T) levels or inactivate its function, improvements in diagnostic and assay technologies, identification of lower therapeutic targets for T, discovery of the relevance of germline genetic mutations and identification of the benefits of sequential and combination therapies.
Methods:
This review discusses the clinical profiles of the most up-to-date options for ADT, best practices for managing patients with advanced PCa and future directions in therapy.
Results and conclusions:
Modern assay technologies reveal that bilateral orchiectomy results in a serum T level of approximately 15 ng/dL as compared to the historical definition of castration of T < 50 ng/dL. Evidence shows that lowering T levels to <20 ng/dL improves patient survival and delays disease progression. Routine monitoring of T in addition to prostate-specific antigen throughout treatment is important to ensure continuing efficacy of T suppression. New drugs that inhibit androgen signaling in combination with traditional ADT suppress T activity to near zero and have significantly improved patient survival. When personalizing ADT regimens physicians should consider a number of factors including initiation and duration of ADT, monitoring of T levels and PSA, the possibility of switching monotherapies if a patient does not achieve adequate T suppression, and consideration of intermittent vs. continuous ADT according to patients' lifestyles, comorbidities, risk factors and tolerance to treatment.
... In 2012, Van der Sluis and colleagues published thought-provoking results showing that LHRH agonist injections lowered testosterone more than surgical castration did in 66 men. 7 The study was limited by a cross-sectional design and a heterogeneous surgical intervention group that included both men undergoing sex-change operations and men with prostate cancer. Thus, further studies to retest and reproduce these findings are warranted. ...
... 18,19 Van der Sluis et al. also addressed the issue of residual testicular tissue after subcapsular orchiectomy by measuring inhibin b in their cross-sectional study showing lower testosterone levels after LHRH agonist therapy compared to surgical castration (subcapsular and total bilateral orchiectomy). 7 Inhibin b was undetectable in all treated men and the authors concluded that differences in serum testosterone were not explained by residual testicular tissue. However, undetectable levels of inhibin b are also possible in cases with retained testosterone production. ...
Purpose:
Recent evidence suggests that reaching the lowest achievable levels of testosterone with androgen deprivation therapy delays disease progression and increases overall survival in men with advanced prostate cancer. The aim of this analysis is to compare the post-treatment serum testosterone levels between patients undergoing subcapsular orchiectomy and patients treated with the luteinizing hormone-releasing hormone agonist triptorelin.
Material and methods:
In this randomized clinical trial, we included 58 consecutive hormone-naive men diagnosed with advanced prostate cancer at Herlev and Gentofte University Hospital, Denmark, from September 2013 to March 2015. Follow-up was 48 weeks. Participants were randomly assigned (1:1) to either subcapsular orchiectomy or triptorelin 22.5 mg given as 24 week depot injections. Androgen status was measured by liquid chromatography tandem mass spectrometry prior to treatment and after 12, 24 and 48 weeks. Between-group differences in achieved hormone levels were analyzed using longitudinal Tobit regressions.
Results:
Triptorelin injections resulted in 29% (95% CI 17.2, 41.7) lower testosterone levels compared to subcapsular orchiectomy (p<.001). A significantly higher proportion of men receiving triptorelin had testosterone levels <20 ng/dL at 12 and 48 weeks compared to men undergoing orchiectomy (97% versus 79% and 100% versus 87%, p<.05). There was no detectable difference in adrenal androgen reductions between treatment groups.
Conclusions:
The use of 24-week depot triptorelin injections results in significantly lower testosterone levels compared to subcapsular orchiectomy. This is the first randomized study to demonstrate a difference in treatment effect between surgical and medical castration on testosterone levels.
... The validation and use of serum testosterone as a surrogate for clinical benefit has been time tested. 9 Intensive research in AR biology and prostate cancer progression has provided strong evidence supporting the enduring link between testosterone suppression and successful treatment of hormone-naïve advanced prostate cancer and, more recently, castration-resistant prostate cancer (CRPC). 10 Clinical data suggest that the optimal level of testosterone after ADT should be the lowest achievable level of testosterone, although rigorous testing of this hypothesis remains to be completed. ...
... 46 After 6 months of primary ADT, although testosterone levels decline and correlate with intraprostatic levels, absolute levels achieved are likely still sufficient to activate the AR. 9,13 Serum PSA levels also correlate strongly with total testosterone levels during primary ADT, suggesting that PSA levels reflect the androgen milieu during ADT. 46 Recent data showed no linear correlation between total testosterone and PSA levels in patients using LHRH analogs, contesting the equivalence of different pharmacologic castrations regarding total testosterone and PSA levels. ...
Testosterone remains a key target in the treatment of advanced prostate cancer. The relationship of free testosterone to prostate cancer treatment and outcomes remains largely unexplored. A consensus of prostate cancer experts was convened in 2013 to review current knowledge surrounding relationship of total and free testosterone to prostate cancer, discuss the free hormone hypothesis, and highlight future avenues for therapeutics. Free testosterone may better reflect prostate cancer tissue androgen levels than serum total testosterone concentration. Free testosterone deserves more research regarding its relation to clinical outcomes.
... Compared to surgical treatment, Luteinising Hormone Releasing Hormone [LHRH] agonists achieved significantly lower levels of serum testosterone [6]. However, the clinical significance of such a difference is not clear. ...
The choice of ADT should be individualized depending on the patient’s clinical indication, life expectancy, compliance and patient’s wishes. The cost of treatment should not be forgotten, more so, in resource-poor settings like Sri Lanka[11]. When counselling patients to decide on the type of ADT,it is important to consider the non-inferiority of surgical androgen ablation to medical forms of ADT.
... Both exogenous and endogenous factors impede the accuracy of these tests for detecting low serum testosterone levels in this population. Hence, liquid chromatography mass spectrometry remains the gold standard [69][70][71][72][73]. ...
Background Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. Objective To present the results from the APCCC 2019. Design, setting, and participants Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. Outcome measurements and statistical analysis The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. Results and limitations Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. Conclusions These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. Patient summary The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
... Both exogenous and endogenous factors impede the accuracy of these tests for detecting low serum testosterone levels in this population. Hence, liquid chromatography mass spectrometry remains the gold standard [69][70][71][72][73]. ...
Background:
Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.
Objective:
To present the results from the APCCC 2019.
Design, setting, and participants:
Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.
Outcome measurements and statistical analysis:
The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.
Results and limitations:
Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.
Conclusions:
These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.
Patient summary:
The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
... Based on 50 year old double-isotope derivative assays, adequate androgen deprivation is defined by circulating testosterone concentrations of < 1.7 nmol/L [7][8][9]. Notably, recent studies applying chemiluminescent immunoassays (IA) indicate that a cut-off at 0.69 nmol/L is more appropriate [10][11][12][13]. While these assays have obvious advantages for clinical laboratories, they tend to lack sensitivity and specificity necessary to accurately quantitate testosterone in low concentration ranges [14][15][16]. ...
Prostate cancer is the most common malignancy among men in the Western world. Treatment of this patient population, e.g. by (chemical) castration, is primarily focused on depletion of tumor-stimulating androgens, with testosterone being the major androgenic hormone. After initial therapy, prostate cancer may progress to metastatic castration-resistant prostate cancer. Anti-hormonal drugs abiraterone acetate and enzalutamide are commonly used to treat patients with this disease as both drugs reduce tumor growth and increase time to tumor progression. To evaluate the pharmacodynamic effects of anti-hormonal drugs in this patient population, we developed an LC–MS/MS method for the quantification of testosterone, dihydrotestosterone, androstenedione, cortisol and prednisone in human plasma. The validated assay ranges from 10-10,000 pg/mL for testosterone and androstenedione, 100–10,000 pg/mL for dihydrotestosterone, 50–5000 pg/mL for cortisol and 500–50,000 pg/mL for prednisone. Intra-assay and inter-assay variabilities were within ±15% of the nominal concentrations for quality control (QC) samples at low, medium and high concentrations and within ±20% at the lower limit of quantification (LLOQ), respectively. The applicability of the method was demonstrated in plasma from patients with metastatic castrated-resistant prostate cancer using either abiraterone acetate or enzalutamide.
... 2,4 With the advent of improved assays, T now can be measured to much lower limits of quantification (LOQ) of ,3 ng/dL. 5 T levels of 20 to 32 ng/dL during ADT are associated with a delay in onset of castrate-resistant PCa (CRPC) and lower risk of death for patients compared with those with higher T levels, 2,6 suggesting the lowest possible serum T should be the objective of ADT. Consequently, in the 2012 Bethesda consensus published by a group of US experts, a 20 ng/dL threshold for serum T during ADT in patients with advanced PCa was recommended, although American Urological Association (AUA) and National Comprehensive Cancer Network (NCCN) guidelines have not adopted this recommendation. ...
Evidence suggests lower nadir testosterone levels during the first year of androgen deprivation therapy improve advanced prostate cancer clinical outcomes. We evaluated pivotal trials for subcutaneously administered leuprolide acetate (1-, 3-, 4-, and 6-month doses) to determine nadir testosterone levels. Pooled analysis showed 99%, 97%, and 91% of patients reached nadir testosterone ≤20, ≤10, and ≤5 ng/dL respectively (median ≤3 ng/dL). Across all available categories, $88% of patients reached nadir testosterone ≤5 ng/dL, and <3% experienced a microsurge. Achievement and maintenance of low nadir testosterone levels may improve progression-free survival and time to onset of castrate-resistant prostate cancer.
... The levels of testosterone assessed by mass spectrometry in these patients were significantly lower than the levels reported by the clinical laboratories using an immunoassay done at the time of the study. This is consistent with literature reporting that immunoassay-based measurement of low levels of testosterone tends to overestimate the levels (19)(20)(21). Although the levels differed from the clinical laboratory, both sets of testosterone levels correlated with outcome. ...
Purpose:
Phenotypic biomarkers are a high priority for patients receiving androgen deprivation therapy (ADT) for prostate cancer given the increasing number of treatment options. This study evaluates serum sex steroids as prognostic biomarkers in men receiving ADT for recurrent prostate cancer.
Experimental design:
Retrospective cohort study of Canadian patients in the PR.7 trial (accrual 1999-2005) who received continuous ADT for biochemical recurrence post-radiotherapy. Patients were excluded with follow-up <2 years or who received estrogens or corticosteroids. Kaplan-Meier and multivariable cox regression analyses adjusted for baseline prognostic factors assessed time to castration resistance prostate cancer(CRPC), prostate cancer survival and overall survival according to tertile of sex steroid measured by mass spectrometry.
Results:
Post-ADT initiation, we measured samples in 219 patients as well as 2 subsequent annual samples in a subset of 101 patients. Testosterone levels correlated with androstenedione (AD) and dihydrotestosterone (DHT), while DHT, AD, androsterone (AST), dehydroepiandrosterone (DHEA) and androstenediol (A5diol) were highly correlated to each other and negatively associated with age. Higher tertiles of estrone(E1) and estradiol(E2) were significantly associated with sooner time to CRPC. In patients with longitudinal samples, increases in serum DHEA and AST were significantly associated with sooner time to CRPC. Limitations include the number of events for some groups.
Conclusions:
Our data suggest the patient hormonal milieu has long-term prognostic value in men receiving ADT for recurrent prostate cancer, including increased levels of E1 and E2 and rising DHEA and AST levels which predict a shorter time to CRPC.
... 1,21 This recommendation to lower the target castrate level follows evidence from more accurate testing techniques showing that the median value of testosterone after surgical castration is actually 0.15 ng/ml or lower, and that failure to achieve testosterone levels <0.2 ng/ml with ADT correlates with reduced time to castrate-resistant prostate cancer and increased mortality. [22][23][24][25] Although regulatory authorities still regard <0.5 ng/ml as the standard castrate level, 1 it is important that the different LHRH agonists demonstrate the ability to provide long-term, stable suppression of testosterone to <0.2 ng/ml, as growing evidence suggests that reaching and maintaining this lower castration level during ADT improves clinical outcomes. 22,23,26 The leuprorelin acetate implant and leuprorelin acetate powder for reconstitution formulations have been shown to achieve durable testosterone suppression to <0.2 ng/ml in recent studies of patients with advanced prostate cancer. ...
Background:
Androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) agonists is well established for the treatment of men with metastatic prostate cancer. As clear differences in efficacy, safety, or tolerability between the available LHRH agonists are lacking, the healthcare management team needs to look to practical differences between the formulations when selecting therapy for their patients. Moreover, as the economic burden of prostate cancer rises alongside earlier diagnosis and improved survival, the possibility for cost savings by using products with specific features is growing in importance.
Methods:
A review was conducted to summarize the information on the different LHRH agonist formulations currently available and offer insight into their relative benefits and disadvantages from the perspectives of physicians, a pharmacist, and a nurse.
Results:
The leuprorelin acetate and goserelin acetate solid implants have the advantage of being ready to use with no requirement for refrigeration, whereas powder and microsphere formulations have to be reconstituted and have specific storage or handling constraints. The single-step administration of solid implants, therefore, has potential to reduce labor time and associated costs. Dosing frequency is another key consideration, as administering the injection provides an opportunity for face-to-face interaction between the patient and healthcare professionals to ensure therapy is optimized and give reassurance to patients. Prostate cancer patients are reported to prefer 3- or 6-monthly dosing, which aligns with the monitoring frequency recommended in European Association of Urology guidelines and has been shown to result in reduced annual costs compared with 1-month formulations.
Conclusions:
A number of practical differences exist between the different LHRH agonist preparations available, which may impact on clinical practice. It is important for healthcare providers to be aware and carefully consider these differences when selecting treatments for their prostate cancer patients.
... 33,34 However, another study showed that GnRH agonists could suppress the average level of serum testosterone more dramatically than surgical castration. 35 Thus, although the effects on testosterone suppression might differ, the anticancer effects between surgical castration and medical castration are similar. A meta-analysis of 10 trials comparing GnRH agonists with surgical castration reported no significant difference in PFS as well as OS, 22 and cardiovascular comorbidity with surgical castration might possibly be lower than that with the GnRH agonist, although this could be the result of bias. ...
Since 1941, androgen deprivation therapy has been the primary treatment for metastatic hormone-sensitive prostate cancer. Androgen deprivation therapy consists of several regimens that vary according to therapeutic modality, as well as treatment schedule. Androgen deprivation therapy initially shows excellent antitumor effects, such as relief of cancer-related symptoms, tumor marker decline and tumor shrinking. However, most metastatic hormone-sensitive prostate cancer cases eventually develop castration resistance and become lethal. Taxanes, such as docetaxel and cabazitaxel, as well as novel androgen receptor-targeting agents, such as abiraterone acetate and enzalutamide, have emerged for metastatic castration-resistant prostate cancer. The concept and principle of primary therapy for metastatic hormone-sensitive prostate cancer has remained unchanged for decades. Recently, upfront docetaxel chemotherapy has been shown to prolong overall survival in men with metastatic hormone-sensitive prostate cancer, and would lead to a paradigm shift in primary pharmacotherapy for metastatic hormone-sensitive prostate cancer. This raises the possibility of upfront use of taxanes, as well as novel androgen receptor-targeting agents combined with androgen deprivation therapy. The present review summarizes the current status of primary pharmacotherapy for metastatic hormone-sensitive prostate cancer, and discusses future perspectives in this field.
... Several HPLC-tandem mass spectrometry (MS-MS) method have been developed for the quantitative analysis of individual serum chemical castration agents and testosterone (8)(9)(10)(11)(12)(13)(14)(15). However, to the best of our knowledge, there have been no trials to measure all the chemical castrations agents as well as testosterone simultaneously because of different chemical characteristics of the compounds. ...
Chemical castration involves administration of drugs to prevent pathological sexual behavior, reduce abnormal sexual drive and treat hormone-dependent cancers. Various drugs have been used for chemical castration; however, substantial interindividual variability and side effects are often observed. In this study, we proposed a useful monitoring method for the application of chemical castration agents using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS). Testosterone, cyproterone acetate, medroxyprogesterone, goserelin acetate, leuprolide acetate and triptorelin acetate were analyzed by UPLC-MS-MS. The target drugs were extracted from serum samples by double protein precipitation using methanol. Testosterone-1,2-d2 and buserelin acetate were used as internal standards. Parameters of analytical performance were evaluated, including imprecision, linearity, ion suppression and detection capabilities. Testosterone measurements were compared with the results of immunoassays. Serum specimens from 51 subjects who underwent chemical castration were analyzed. All drugs and testosterone were well extracted and separated using our method. The method was essentially free from potential interferences and ion suppression. Within-run and between-run imprecision values were <15%. The lower limits of quantification were 0.125 and 0.5-1.0 ng/mL for testosterone and other drugs, respectively. Good correlations with pre-existing immunoassays for testosterone measurement were observed. Sera from subjects who underwent androgen deprivation therapy showed variable levels of drugs. We successfully developed a UPLC-MS-MS-based monitoring method for chemical castration. The performance of our method was generally acceptable. This method may provide a novel monitoring strategy for chemical castration to enhance expected effects while reducing unwanted side effects.
... Medical castration has been shown to produce lower levels of testosterone than sur- gical castration. Mass spectrometry measurements of serum testosterone levels show that surgical castration results in approximately 10 ng/dL compared to 4 ng/dL for medical castration [21]. Gonadotropin-releasing hormone (GnRH) agonists, such as Lupron or Zoladex, initially cause increased levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and subsequently cause an increase in circu- lating androgens. ...
Prostate cancer is the most common and second most lethal cancer in men. The majority of prostate cancers are histologically similar acinar adenocarcinomas and rely on androgen dependent signaling for their development and progression. Androgen deprivation therapy is a mainstay of treatment regimens and we discuss recent advancements in androgen deprivation therapy. Recent advances in defining the genetic landscape of prostate cancer have shown that the depth of genetic heterogeneity surpasses what can be seen histologically and has the ability to redefine treatments. TMPRSS2-ETS family fusion proteins are unique to prostate cancer and we discuss their role in carcinogenesis, prognosis, and the development of TMPRSS2-ETS family gene fusion targeted therapy. Inactivation of the tumor suppressor PTEN leads to activation of the PI3K/Akt/mTOR pathway and we discuss the prognostic and treatment implications. Molecular genetic analysis has recently demonstrated that clinically aggressive high grade neuroendocrine prostate carcinomas contain a high prevalence of overexpression of Aurora A kinase and N-myc. We discuss the role of Aurora A kinase and N-myc in the development of the aggressive neuroendocrine phenotype and the development of targeted inhibitors of this specific genetic subtype. Lastly, we briefly discuss emerging genetic subtypes defined by either SPINK1 overexpression, CHD1 inactivation, or SPOP mutations. By reviewing the associations between the morphologic features and the molecular genetics of prostate cancer, we hope to provide insight and guidance to the emerging options for targeted therapy.
Introduction: Metastatic disease is found in up to 20% of prostate cancer (PCa) cases at diagnosis. Since their introduction in the 1980s, long acting gonadotropin-releasing hormone (GnRH) analogues, administered subcutaneously or intramuscularly every 1–6 months have widely replaced bilateral orchidectomy as the method of castration for this cohort of patients. Recent evidence suggests that surgical castration confers a superior side-effect profile and cost. We aimed to perform a systematic review and meta analysis to compare these two treatment methods particularly in terms of survival, side-effect profile and cost-effectiveness.
Methods: A systematic review of the literature was performed for studies comparing medical and surgical castration for metastatic PCa. Outcome measurements included overall survival, side-effect profile and cost.
Results: Fifteen studies on 63,682 participants (n = 59,045 for medical and n = 4637 for surgical) met inclusion criteria. Our analysis demonstrated a trend towards significance in overall survival rates in favour of surgical castration (hazard ratio = 0.89, 95% confidence interval (CI) = 0.79 to 1.01, p = 0.06), a trend towards significance in cardiovascular complications in favour of the surgical group (odds ratio (OR) = 0.79, 95% CI = 0.62 to 1.00, p = 0.05) and a significantly lower nadir prostate-specific antigen (PSA) level in favour of medical castration (MD PSA 1.17 less in medical castration group, 95% CI = 0.67 to 1.67, p < 0.01).
Conclusion: Surgical castration appears to be a safe, feasible and efficacious alternative to medical castration, with evidence to suggest a potential survival benefit and limited evidence of a financial benefit in the treatment of men with metastatic PCa. Further studies are required to further quantify the financial burden of one method over another, as well as to identify which subgroup of patients respond best to each method of castration.
Background
Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy.
Methods
Transgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3, 12 months, and 2-4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosteronesulfate (DHEAS) and androstenedione (A4) were measured using LC-MS/MS.
Results
After three months of GAHT, mean TT, cFT and A4 decreased by 18.4 nmol/L (95%CI -19.4, -17.4, p < 0.001) i.e. -97.1%, 383 pmol/L (95%CI -405, -362, p < 0.001) i.e. -98.3% and 1.2 nmol/L (95%CI -1.4, -1.0, p < 0.001) i.e. -36.5% respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95%CI -9.7, -5.1) i.e -28.0% and 1.8 µmol/L (95%CI -2.2, -1.4) i.e. -20.1%, respectively, after one year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS and A4 compared those who did not undergo gonadectomy.
Conclusions
Our findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.
Objectives
Testosterone testing is relevant for evaluating castration adequacy and diagnosis of castration-resistant prostate cancer (PCa). However, the recommended testosterone cut-off of 1.7 nmol/L (50 ng/dL) to define adequate castration is based on consensus and not validated for the automated immunoassays (AIA) used in today’s medical laboratories. Furthermore, appropriate population intervals have not been determined by a state-of-the-art assay. We investigated the analytical suitability of this cut-off and the accuracy of the present-day AIAs for testosterone analysis in castrated PCa patients.
Methods
Leftover serum from 120 PCa patients castrated with luteinizing hormone-releasing hormone agonists was analysed for testosterone by five methods: Architect i2000 (Abbott), Access (Beckman), Cobas 6000 (Roche), Atellica (Siemens), LC-MS/MS. For all assays, the castration 95th, 97.5th and 99th percentile upper limits were determined. Furthermore, Passing-Bablok regression, mean bias and Spearman’s correlation coefficients were compared to the LC-MS/MS method and total error based on biological variation.
Results
All castration upper limits, ranging from 0.472 nmol/L (LC-MS/MS) to 1.25 nmol/L (Access) (95% percentile), were significantly lower than the current castration cut-off (1.7 nmol/L). Slopes of Passing-Bablok regressions comparing the AIA with the LC-MS/MS method ranged from 1.4 (Cobas and Atellica) to 3.8 (Access). The Architect showed the highest correlation with LC-MS/MS (ρ=0.58). All AIA failed to meet the desirable total error criterion.
Conclusions
These results suggest that a lower general testosterone castration cut-off may be more appropriate in evaluating the adequacy of castration in PCa and that present-day AIA lack analytical accuracy to quantify testosterone levels in castrated PCa.
Testosterone is an essential steroid hormone associated with a wide variety of biological processes in humans. In prostate cancer, androgen signaling is an important driver of tumor cell growth. Depletion of gonadal testosterone, achieved by surgical or chemical castration, prevents androgenic signaling and temporally reduces, stops or reverses tumor growth before inevitable progression to castration-resistant prostate cancer occurs. Additional treatment strategies targeting androgenic signaling have become available, although these are without curative intent. While circulating testosterone is also associated with disease risk and potential clinical utility, the main use in the clinical lab is monitoring adequate castration and subsequent resistance to therapy. Adequate castrate testosterone concentrations are currently based on over 50 year-old double-isotope derivative assays that are disputed in automated immunoassay (IA) analysis. The debate has been further fueled with the introduction of mass spectrometry-based assays for testosterone, offering a substantial increase in sensitivity and specificity. In this review, we discuss testosterone regulation and androgen deprivation therapy in prostate cancer. We provide an overview of the developments in testosterone analysis for monitoring adequate castration and resistance to therapy. Current clinical practice and future clinical utility will be discussed. Finally, clinical and research recommendations will be presented.
Background:
A sensitive liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was used to monitor serum testosterone levels in castrated prostate cancer patients. We subsequently performed an observational and retrospective study to estimate the within- and between-subject biological variation of these patients.
Methods:
In total, 474 samples from 72 prostate cancer patients in the Netherlands receiving either chemical castration (CAS) or castration plus enzalutamide (ENZA) treatment were selected for data analysis. ANOVA was performed to estimate analytical variation (CVA) and within-patient variation (CVI). A nested ANOVA was applied to estimate between-patient variation (CVG). From these data, the reference change value (RCV) and analytical performance specifications (APS) were calculated.
Results:
Testosterone levels were significantly higher in the ENZA group (0.318 vs. 0.191 nmol/L, p<0.005) than the CAS group. Overall, variation components were estimated at 6.1%, 24.6% and 60.3% for CVA, CVI and CVG, respectively. Both groups showed high individuality (<0.6). The RCV was 70.3% for all patients. Desirable APS were 12.3% for imprecision, 16.3% for bias and 26.4% for total error.
Conclusion:
The generated APS are valuable for sensitive testosterone assays and the high individuality indicates that castrated testosterone levels can be studied as a predictive or prognostic biomarker in prostate cancer patients.
Spinal and bulbar muscular atrophy (SBMA) is a progressive hereditary neuromuscular disease caused by the testosterone-dependent accumulation of pathogenic polyglutamine-expanded androgen receptor protein. A 41-year-old man with SBMA received the androgen deprivation agent leuprorelin acetate for 7 years in clinical trials and underwent castration following the trial. Suppression of testosterone levels for 14 years resulted in a slower disease progression, as measured prospectively with quantitative measurements, than the historical control data reported in previous studies. This suggests that long-term androgen deprivation delays disease progression in SBMA.
This narrative review presents an overview of present knowledge on fertility and reproductive hormones changes in aging men, the factors driving and modulating these changes, their clinical consequences, and benefits and risks of testosterone (T) therapy.
Aging is accompanied by moderate decline of gamete quality and fertility. Population mean levels show mild total T decline, SHBG increase, steeper free T decline, and moderate LH increase with important contribution of comorbidities (e.g. obesity) to these changes. Sexual symptoms and lower hematocrit are associated with low T and partly responsive to T therapy. Relationship of serum T with body composition and metabolic health is bidirectional; limited beneficial effects of T therapy on body composition have only marginal effects on metabolic health and physical function. Skeletal changes are associated primarily with estradiol and SHBG. Cognitive decline is not consistently linked to low T and not improved by T therapy. Although limited evidence links moderate androgen decline with depressive symptoms, T therapy has small beneficial effects on mood, depressive symptoms and vitality in elderly with low T. Not optimal T (and/or DHT) has been associated with increased risk of stroke, but not of ischemic heart disease, whereas association with mortality probably reflects that low T is a marker of poor health. Globally, neither severity of clinical consequences attributable to low T, nor nature and magnitude of beneficial treatment effects justify the concept of some broadly applied ‘T replacement therapy’ in older men with low T. Moreover, long-term safety of T therapy is not established.
In the 1940s, Charles Huggins et al. published a paper describing the clinical benefits of surgical castration and estrogen administration in prostate cancer patients. Later, Huggins was awarded the Nobel Prize to acknowledge the importance of his findings in this field. Since that time, androgen deprivation therapy (ADT) remains a standard therapy for metastatic prostate cancer. Although the main aim of ADT is the control of the serum testosterone (TST) level below the castration level, a series of evidences indicated the clinical significance of controlling the serum TST level even below the standard castration level. In terms of TST production, multiple pathways exist, such as “classical pathway” and “backdoor pathway.” Upregulation of such pathways, even inside the tumor, contributes to the acquisition of castration resistance. Thus, monitoring serum TST levels provides us further understanding of tumor behavior in individual patients. In this chapter, we will discuss the prognostic significance of monitoring serum TST levels in primary ADT for prostate cancer.
Testosterone suppression, achieved through orchiectomy or medically-induced androgen deprivation therapy (ADT), is a standard treatment for men with recurrent and metastatic prostate cancer. Current assay methods demonstrate the capacity for testosterone suppression to <0.7 nmol/l, and clinical data support improved outcomes from ADT when lower levels are achieved. Practical clinical guidelines are warranted to facilitate adoption of 0.7 nmol/l as the new standard castrate testosterone level.A pan-Canadian group of experts, representing diverse clinical specialties, identified key clinical issues, searched and reviewed relevant literature, and developed consensus statements on testosterone suppression for the treatment of prostate cancer. The expert panel found that current evidence supports the clinical benefit of achieving low testosterone levels during ADT, and encourage adoption of ≤0.7 nmol/l as a new castrate level threshold. The panel recommends regular monitoring of testosterone (e.g., every 3–6 months) and PSA levels as clinically appropriate (e.g., every 3–6 months) during ADT, with reassessment of therapeutic strategy if testosterone is not suppressed or if PSA rises regardless of adequate testosterone suppression. The panel also emphasizes the need for greater awareness and education regarding testosterone assay specifications, and strongly promote the use of mass spectrometry-based assays to ensure accurate measurement of testosterone at castrate levels.
Steroid hormones play a central role in the maintenance and progression of prostate cancer. The androgen receptor is the primary driver of tumor cell proliferation and is activated by the androgens testosterone and 5α-dihydrotestosterone. Inhibition of this pathway through medical or surgical castration improves survival in the majority of advanced prostate cancer patients. However, conversion of adrenal androgen precursors and alternative steroidogenic pathways have been found to contribute to tumor progression and resistance to treatment. The emergence of highly accurate detection methods allows us to study steroidogenic mechanisms in more detail, even after treatment with potent steroidogenic inhibitors such as the CYP17A1 inhibitor abiraterone. A clear overview of steroid hormone levels in patients throughout the local, metastatic and castration-resistant stages of prostate cancer and treatment modalities is key towards a better understanding of their role in tumor progression and treatment resistance. In this review we summarize the currently available data on steroid hormones that have been implicated in the various stages of prostate cancer. Additionally, this review addresses the implications of these findings, highlights important studies in this field and identifies current gaps in literature.
Introduction:
Reductions in testosterone concentration play a significant role in the treatment of prostate cancer. We studied the role of testosterone as a prognostic marker for advanced prostate cancer (stage C or higher) treated with primary androgen-deprivation therapy (ADT).
Patients and methods:
A total of 348 patients were treated using ADT as first-line therapy for prostate cancer at Chiba University Hospital between 1999 and 2016. Of these, 222 patients with advanced prostate cancer (stage C or higher) were enrolled onto this study. The prognostic values of serum testosterone level and other clinical factors were evaluated in association with prostate-specific antigen (PSA), progression-free survival during first-line therapy, and overall survival.
Results:
Median age was 73 years. PSA at baseline was 86 ng/mL. Gleason scores of ≤ 6, 7, 8, and ≥ 9 were seen in 2.3%, 19.4%, 21.2%, and 41.9%, respectively. Mean follow-up was 60.5 months. Median testosterone at baseline was 482 ng/dL and nadir testosterone was 13 ng/dL. No variable associated with testosterone predicted progression-free survival. With regard to overall survival, multivariate analysis identified nadir testosterone ≤ 20 ng/dL (hazard ratio = 0.44, P = .026) and testosterone reduction ≥ 480 ng/dL (hazard ratio = 0.35, P = .030) as independent prognostic factors. With regard to progression-free survival, multivariate analysis identified nadir PSA ≤ 0.1 ng/mL (hazard ratio = 3.07, P < .001), presence of lymph node metastasis (hazard ratio = 1.67, P = .017), and time to nadir PSA (hazard ratio = 0.30, P < .001) as independent prognostic factors.
Conclusion:
Our data suggested both nadir testosterone (< 20 ng/dL; P = .026) and testosterone reduction (≥ 480 ng/dL; P = .030) to be key prognostic factors for primary ADT in advanced prostate cancer in Japanese men.
Transplantation of hormone-producing cells is an experimental endocrine dysfunction treatment. The present study investigated the effects of orchidectomy (OE) and transplantation of interstitial cell suspension (ICS) on rat sexual behavior. Adult experimental animals were divided into two populations. One of these populations had sexual experience before the experiment and the other did not. Each population was divided into three groups: control group and two orchidectomized groups. One of the orchidectomized groups was treated with ICS, and the other was treated with the vehicle. The changes in the sexual behavior were investigated on the following parameters: mount latency (ML), intromission latency (IL), ejaculation latency (EL), mount frequency (MF), intromission frequency (IF), copulatory efficacy (CE), and IF/EL ratio. The investigation of these changes lasted 4 weeks after ICS transplantation. The parameters of sexual behavior reflected a decrease in sexual function after OE at the beginning of the observation, especially for the animals that did not have a sexual experience. However, it was shown that sexual activity increased in the following 4 weeks. We have indicated that the loss of gonads attenuated the capacity to acquire sexual experience; nonetheless, it did not mean that the animals completely lost this capacity. Transplantation of ICS facilitated the maintenance of male sexual behavior after OE, fractionally enlarged the size of regressed seminal vesicles of the animals, and increased the free testosterone (T) level. These findings suggest the ICS can be considered as a temporal source of androgens, which can facilitate a restoration of sexual activity.
Biochemical assessments of androgen status (hyper- or hypoandrogenism) are usually based on serum testosterone concentrations. According to the free hormone hypothesis, sex hormone-binding globulin (SHBG) determines free and bioavailable testosterone concentrations. Previous studies have suggested that in vitro androgen bioassay results may also be influenced by SHBG and correlate with free or bioavailable testosterone concentrations. To test this hypothesis, we established a stable HEK293 cell line with high expression of the human androgen receptor (AR) and a luciferase reporter downstream of a classical androgen response element. Importantly, we demonstrate that bioassay results are sensitive to dilution effects which increase apparent bioactivity in an SHBG-dependent manner. We therefore adopted a method using undiluted serum, which reduced cell proliferation but did not significantly affect the luciferase signal, cell viability or cytotoxicity. To correct for serum matrix effects, we applied signal correction based on internal controls with AR agonists or antagonists. Using this method, we provide direct evidence that in vitro androgen bioactivity reflects the inhibitory effects of SHBG, and correlates with free or bioavailable testosterone concentrations in adult hypogonadal men receiving androgen replacement therapy. In men receiving anti-androgens, serum bioactivity decreased tenfold while serum testosterone concentrations decreased only four-fold. Further pilot results in prostate cancer patients showed that androgen synthesis inhibitors result in more complete inhibition of androgen bioactivity than gonadorelin-based androgen deprivation therapy, even in patients whose testosterone concentrations were undetectable by mass spectrometry. We conclude that in vitro androgen reporter bioassays are useful tools to study how androgen bioactivity in serum is determined by androgens, anti-androgens as well as SHBG, provided that dilution and matrix effects are accounted for.
Objective:
To determine whether an LHRH agonist, ATRIGEL(®) polymer-delivered, subcutaneous, leuprolide acetate (ADSC-LA) formulations suppressed testosterone to levels ≤20 ng/dL.
Subjects/patients and methods:
Data from four open-label, fixed-dose studies were evaluated. Male patients aged 40-86 years with advanced prostatic adenocarcinoma, whom had not undergone prior ADT, were treated with a depot formulation of ADSC-LA: 7.5 mg [1 month (1M); N=120], 22.5 mg [3 months (3M); N=117], 30 mg [4 months (4M); N=90], or 45 mg [6 months (6M); N=111]. Serum testosterone was sampled at screening, baseline, 2, 4, 8 hours post-dosing, days 1, 2, 3, 7, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (24 weeks for 1M and 3M, 32 weeks for 4M, and 48 weeks for the 6M dose). The primary analyses were mean serum testosterone levels and proportion of patients who achieved serum testosterone levels ≤20 ng/dL.
Results:
Mean serum testosterone levels at the end of study were consistently ≤20 ng/dL in each study (6.1±0.4, 10.1±0.7, 12.4±0.8, 12.6±2.1 for the 1M, 3M, 4M, and 6M doses, respectively). A high proportion of patients (94%, 90%, 92%, 96% for 1M, 3M, 4M, and 6M doses, respectively) achieved testosterone levels ≤20 ng/dL within 6 weeks, and 90-97% of patients in all studies maintained testosterone ≤20 ng/dL from weeks 6-24.
Conclusions:
Recent studies have demonstrated improved outcomes in prostate cancer patients who consistently attained a more rigorous level of testosterone suppression (≤20 ng/dL) with androgen deprivation therapy (ADT) than the historical standard (≤50 ng/dL). All doses of ADSC-LA rapidly achieved and maintained mean serum testosterone to the more rigorous target level of T ≤20 ng/dL. These data suggest that ADSC-LA delivers equivalent testosterone suppression as achieved by surgical castration. This article is protected by copyright. All rights reserved.
Background:
Neutrophilic dermatoses refer to a group of cutaneous inflammatory disorders characterized by neutrophilic infiltration of the skin. Neutrophilic dermatoses have been reported in association with various conditions including autoimmune diseases, inflammatory bowel diseases, and neoplasia. In the later condition, myeloproliferative disorders and monoclonal gammopathy (monoclonal immunoglobulin [MIg]) are the most frequent. Only few data are available in case of neutrophilic dermatoses associated with MIg regarding the pathophysiology and the clinical outcome.
Objective:
We sought to gain further insight into clinical and biological aspects of neutrophilic dermatoses associated with MIg.
Methods:
We report a retrospective series of 26 patients with neutrophilic dermatoses associated with MIg focusing on clinical and biological aspects, with a study of a large panel of cytokines, chemokines, and adhesion molecules.
Results:
This study reveals an association between MIg IgA isotype and neutrophilic dermatoses, and a specific inflammatory pattern including elevated interleukin 6, vascular endothelial growth factor, monocyte chemotactic protein-1, epidermal growth factor, and intercellular adhesion molecule-1.
Limitations:
This is a retrospective study from a single institution with a limited number of participants.
Conclusion:
Our data highlight a strong association between IgA isotype and neutrophilic dermatoses, and the existence of a specific inflammatory profile involving several molecules.
Luteinizing hormone-releasing hormone agonists such as leuprolide acetate (LA) are the most frequently utilized treatment of advanced prostate cancer as the regimen for achieving androgen deprivation therapy (ADT). The efficacy of LA is determined by extent of testosterone (T) suppression in prostate cancer patients. Although, the historical castrate T suppression target has been defined as < 50 ng/dl, this level may not be as low as required to deliver equivalent suppression as achieved by surgical castration. Recent studies have demonstrated that a T level as low as 20 ng/dl may produce improved clinical outcomes.
LA is available in long-acting formulations that deliver active drug over the course of 1-6 months from a single-dose administration. The technologies utilized to provide sustained drug delivery differ: one mode of administration uses microspheres, which encapsulate the drug and are injected as a suspension intramuscularly; another mode of administration uses a liquid polymer that creates a single, solid depot after injection subcutaneously. This article will review the safety and efficacy of both 6-month LA formulations, as well as their impact in prostate cancer treatment.
As the understanding of optimal T castrate level evolves and may be refined pending new data from contemporaneous trials, achievement and maintenance of T levels well below 50 ng/dl may be important in evaluating potential differences in ADT regimens.
To examine the clinical significance of long-term serum testosterone (TST) monitoring for predicting the prognosis of prostate cancer patients treated with combined androgen blockade (CAB).
225 patients who underwent CAB as first-line therapy for prostate cancer were retrospectively analyzed. The prognostic values of serum TST levels and other clinical factors were evaluated with respect to PSA progression-free survival (PFS) and overall survival (OS).
The patients' median age was 73.0 years. The median PSA was 42.6 ng/mL. The median follow-up was 45.8 months. No variable associated with TST was predictive of PFS. With regard to OS, on univariate analysis, nadir TSTs <16 (p = 0.0190), < 20 (p = 0.0020) and < 32 (p = 0.0146) ng/dL were significant together with other clinical factors. In contrast, nadir TSTs < 8 and < 12 ng/dL were not significant. Multivariate analysis showed that nadir TST < 20 ng/dL was the significant prognostic factor (p = 0.0048). In addition, time to nadir TST was about 1 year (11.3 months); the patients were divided into rapid type and slow type, based on time to TST < 20 ng/dL before and after six months, respectively. No significant difference in OS was observed between the two types. The present results suggest that the critical factor for prognosis was not a rapid decrease, but whether nadir TST level achieved < 20 ng/dL.
Nadir TST 20 ng/dL was the most significant cut-off level for OS in Japanese prostate cancer patients treated with CAB.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Androgen and androgen receptor (AR) play a critical role in the development of prostate cancer. Androgen deprivation therapy (ADT) has become the therapeutic mainstay for patients with metastatic prostate cancer. ADT can reduce the serum testosterone level from the normal range between 500 and 600 ng/dl to the castrate level. Following surgical castration, the serum testosterone level decreases to less than 20 ng/dL (0.69 nmol/L) in about three quarters of the patients. Although insufficient suppressions of the serum testosterone level following ADT have not been well recognized to date, the failure in achieving the castrate level of testosterone may have an adverse impact on survival in men with prostate cancer. Although circulating testosterone levels following castration do not necessarily reflect the amount of intraprostatic testosterone or dihydrotestosterone, testosterone during ADT mainly derives from intratumorally synthesized precursors and adrenal androgens. The advent of new agents represented by abiraterone acetate and enzalutamide, which target adrenal or intraprostatic androgen biosynthesis and AR signaling, respectively, has retrieved interest in testosterone levels during ADT. We critically reviewed androgen metabolism and its significance in prostate cancer biology and treatment to promote their better understanding and management of men with prostate cancer.
A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course.
Patients with prostate cancer often receive androgen deprivation therapy (ADT) as part of their treatment regimen. However, treatment with ADT causes multiple side effects, including reduced bone mineral density (BMD), lower lean body mass, and a higher risk for fractures. Several organizations provide clinical practice guidelines for osteoporosis screening, prevention, and treatment in this population, but adherence to these guidelines remains low. Areas for improvement in provider adherence include baseline and follow-up BMD testing, as well as counseling regarding healthy bone behaviors such as calcium/vitamin D intake, lifestyle changes, and physical exercise. Comparison of osteoporosis care in breast cancer and non-oncology populations shows that suboptimal bone health care is not isolated to prostate cancer. A summary of the literature examining improvements in patient adherence and provider delivery of bone health care is included in this review, but high-quality studies are lacking. Patients may be the most receptive to written educational information delivered at or near the time of ADT initiation. Involvement of a primary care practitioner and oncologist in care delivery is associated with higher BMD test use. Institution-level programs that automatically initiate osteoporosis screening and management may be effective at reducing the incidence of hip fracture. Lastly, suggestions are provided for future approaches to knowledge translation and quality of care studies to improve bone health.
Androgens and the androgen receptor play a role in the progression of prostate cancer. Androgen deprivation therapy (ADT) is a mainstay in the treatment of metastatic prostate cancer. ADT is expected to reduce serum testosterone levels from a normal level of about 500 to 600ng/dl (17.3-20.8nmol) down to castration levels. Traditionally, castration was considered to be achieved if testosterone levels were lowered to a threshold of 50ng/dl (1.73nmol/l), a definition determined more by measurement methods derived from the use of old assay methods than by evidence. Serum testosterone levels in three-quarter patients after surgical castration drop to less than 20ng/dl (0.69nmol/l). Ineffective suppression of testosterone is currently poorly recognized and may possibly have an effect of prostate cancer mortality. Persistent levels of serum testosterone after castration are mainly derived from adrenal androgens. Furthermore, the arrival of new therapies targeting androgen synthesis and androgen receptor activity has renewed interest on serum testosterone. This review discusses the biosynthetic pathway for androgen synthesis in humans and provides a comprehensive review of serum testosterone levels after surgical or medical castration. This review assesses serum testosterone levels after surgical castration and different pharmacologic castration in patients with prostate cancer under ADT, and ineffective testosterone suppression. The author proposes methods to better lower serum testosterone levels during ADT.
We seek to determine if testosterone levels below the accepted castration threshold (50 ng/dL) have an impact on time to progression to castrate-resistant prostate cancer (CRPC).
This is a prospective cohort series of patients undergoing androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone agonist or antagonist at a tertiary centre from 2006 to 2011. Serum testosterone level was assessed every 3 months. Patients with any testosterone >50 ng/dL were excluded. Patients were stratified into groups based on those achieving mean testosterone levels <20 ng/dL and <32 ng/dL. Progression to CRPC was assessed with the Kaplan-Meier method and compared with the log-rank test.
A total of 32 patients were included in this study. Mean patient follow-up was 25.7 months. Patients with a 9-month serum testosterone <32 ng/dL had a significantly increased time to CRPC compared to patients with testosterone 32 to 50 ng/dL (p = 0.001, median progression-free survival (PFS) 33.1 months [<32 ng/dL] vs. 12.5 months [>32 ng/dL]). Patients with first year mean testosterone <32 ng/dL also had a significantly increased time to CRPC compared to 32 to 50 ng/dL (p = 0.05, median PFS 33.1 months [<32 ng/dL] vs. 12.5 months [32-50 ng/dL]). A testosterone <20 ng/dL compared to 20 to 50 ng/dL did not significantly predict with time to CRPC.
This study supports a lower testosterone threshold to define optimal medical castration (T <32 ng/dL) than the previously accepted standard of 50 ng/dL. Testosterone levels during ADT serve as an early predictor of disease progression and thus should be measured in conjunction with prostate-specific antigen.
We examined the serum levels of testosterone (T) (total and bioavailable) dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prostate-specific antigen (PSA) in men receiving treatment with luteinizing hormone releasing-hormone (LHRH) agonists for metastatic prostate cancer. In doing this, we want to determine the efficacy of these agents in lowering T levels and whether a possible relationship exists between PSA values, as a surrogate measure of tumour activity, and hormone levels.
This was a single centre prospective study of patients on LHRH agonists. Of all the 100 eligible patients, 31 did not qualify (10 were receiving their first injection, 13 were on intermittent hormonal therapy, 7 refused to enter the trial and 1 patient's blood sample was lost). Therefore in total, 69 patients were included in the final analysis. Each patient had their blood sample drawn immediately before the administration of a LHRH agonist. The new proposed criteria of <20 ng/dL (0.69 nmol/L) of total testosterone was used to define optimal levels of the hormone in this population.
Of the 69 patients, 41 were on goserelin injections, 21 on leuprolide, and 7 on buserelin. There was no statistical difference in hormone levels between any of the medications. Overall, 21% of patients failed to reach optimal levels of total testosterone. PSA levels were higher in this group. There was a statistically significant correlation between PSA and testosterone levels, as well as between PSA and FSH. Serum levels of PSA, however, did not correlate with those of bioavailable testosterone.
Failure to reach optimal levels of testosterone occurs in patients on LHRH agonist therapy. Higher PSA values are more commonly found in patients with suboptimal levels of testosterone receiving LHRH analogs, but the clinical importance of this finding has not been established. There is no significant difference with respect to hormonal levels reached among patients on a variety of LHRH agonists. Total testosterone determinations should be considered in patients on LHRH agonist therapy, particularly when the PSA values begin to rise since it may lead to further beneficial hormonal manipulation.
Objective:
To evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer.
Materials and methods:
A total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥ 3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated.
Results:
The median serum testosterone concentration of the patients with a BMI <25 kg/m(2) was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m(2) had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m(2) had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men.
Conclusion:
Using an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted.
Purpose:
Prostate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings.
Methods:
In vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration-resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily.
Results:
Testosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth.
Conclusions:
Despite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted.
Objectives:
Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC).
Methods:
The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.
Results:
Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values > 0.2 ng/ml following radical prostatectomy (RP) and > 2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels < 0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and 11C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is < 2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m(2) every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications.
Conclusion:
The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.
Testosterone assays are widely used. However, deficiencies in these assays limit their broad and effective implementation and threaten the health of those patients whose medical care relies upon its accurate measurement. Furthermore, the translation of research findings into information useful for patient care, such as new evidence-based clinical guidelines, is not possible unless both research and clinical assays are held to higher standards than are currently required. A group of concerned stakeholders was convened to address this problem.
Representatives of multiple professional societies, government, and industry, having a stake in ensuring that testosterone levels are measured accurately and reliably, met to identify goals, objectives, and actions necessary to bring about the standardization of assays for testosterone.
To ensure highly accurate testosterone testing that will result in improved diagnosis, treatment, and prevention of disease through the use of standardized assays, a series of recommendations were agreed upon. The recommendations included the following: technical improvements for assay standardization; education of health care providers, patients, and all others concerned with testosterone testing; plans to encourage all concerned journals, government agencies, and health insurance companies to support this effort; and encouragement to manufacturers to develop better and more cost effective assays.
A preliminary timeline was set out to implement the recommendations of the Group.
In addition to their expression on pituitary cells, receptors for luteinizing hormone-releasing hormone (LH-RH) are found on most prostate cancer cells. These tumoral LH-RH receptors mediate the direct cytotoxic effects of LH-RH analogs and are potential therapeutic targets. Although pituitary LH-RH receptors are downregulated following prolonged exposure to LH-RH agonists, there is no evidence that tumoral receptors behave in a similar manner. To better characterize expression of tumoral LH-RH receptors, specimens of prostate cancer from various cohorts of patients were analyzed.
Surgical specimens were obtained from untreated patients with prostate cancer and from patients with metastatic castration-resistant prostate cancer previously treated with bilateral orchiectomy. To address the possibility of receptor downregulation, two additional cohorts of patients who had been previously treated with LH-RH agonists were included. One group received neoadjuvant therapy prior to prostatectomy, and the other group was treated for metastatic disease with LH-RH agonists and, at progression, required palliative resection of the prostate. Lymph node metastases from previously untreated patients were subjected to similar analysis.
Expression of LH-RH receptors was found in most specimens. The relative expression of LH-RH receptor mRNA in untreated patients was greater in patients whose tumor had received a Gleason score <8.
LH-RH receptor expression persisted despite prolonged exposure to LH-RH agonists. These findings support the concept of targeting cytotoxic LH-RH analogs to prostatic LH-RH receptors, using these receptors to gain entry into cancer cells to deliver a hybridized cytotoxic moiety for the treatment of prostate cancer.
Commercially available testosterone immunoassays give divergent results, especially at the low concentrations seen in women. We compared immunoassays and a nonimmunochemical method that could quantify low testosterone concentrations.
We measured serum testosterone in 50 men, 55 women, and 11 children with use of eight nonisotopic immunoassays, two isotopic immunoassays, and isotope-dilution gas chromatography-mass spectrometry (ID/GC-MS).
Compared with ID/GC-MS, 7 of the 10 immunoassays tested overestimated testosterone concentrations in samples from women; mean immunoassay results were 46% above those obtained by ID/GC-MS. The immunoassays underestimated testosterone concentrations in samples from men, giving mean results 12% below those obtained by ID/GC-MS. In women, at concentrations of 0.6-7.2 nmol/L, 3 of the 10 immunoassays gave positive mean differences >2.0 nmol/L (range, -0.7 to 3.3 nmol/L) compared with ID/GC-MS; in men at concentrations of 8.2-58 nmol/L, 3 of the 10 immunoassays tested gave mean differences >4.0 nmol/L (range, -4.8 to 2.6 nmol/L).
None of the immunoassays tested was sufficiently reliable for the investigation of sera from children and women, in whom very low (0.17 nmol/L) and low (<1.7 nmol/L) testosterone concentrations are expected.
Recent developments in the field of mass spectrometry have provided the accuracy and sensitivity to evaluate very-low-abundance steroids such as testosterone in female and pediatric patients. In this issue of Clinical Chemistry , Taieb et al. (1) present the most comprehensive evaluation of automated testosterone immunoassays to date. They compared 10 commercially available immunoassays with isotope-dilution gas chromatography–mass spectrometry (ID-GC/MS) and reached the inescapable conclusion that testosterone immunoassay results for specimens from females are inaccurate. Similar data have been reported for individual testosterone immunoassays previously (2), but Taieb et al. (1) are the first to show that for every commercially available testosterone assay studied, the values are in error—by a factor of 2 on average and in some cases by a factor of almost 5. Are assays that miss target values by 200–500% meaningful? Guessing would be more accurate and additionally could provide cheaper and faster testosterone results for females—without even having to draw the patient’s blood.
By limiting all guesses to a narrow range, e.g., 2.04–2.44 nmol/L, the results would rarely be off by more than a factor of 3. Using a random number generator, we generated values close to the average female concentration measured by Taieb et al. (they were kind …
The objective of the study was to evaluate the current state of clinical assays for total and free testosterone.
The five participants were appointed by the Council of The Endocrine Society and charged with attaining the objective using published data and expert opinion.
Data were gleaned from published sources via online databases (principally PubMed, Ovid MEDLINE, Google Scholar), the College of American Pathologists, and the clinical and laboratory experiences of the participants.
The statement was an effort of the committee and was reviewed in detail by each member. The Council of The Endocrine Society reviewed a late draft and made specific recommendations.
Laboratory proficiency testing should be based on the ability to measure accurately and precisely samples containing known concentrations of testosterone, not only on agreement with others using the same method. When such standardization is in place, normative values for total and free testosterone should be established for both genders and children, taking into account the many variables that influence serum testosterone concentration.
The recent interest of clinical laboratories in developing serum testosterone assays based on isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) stems from the lack of accuracy of direct immunoassays. In this study, we assessed the accuracy and state of standardization (traceability) of 4 published ID-LC-MS/MS procedures in a method comparison with an ID-gas chromatography (GC)-MS reference measurement procedure listed in the database of the Joint Committee for Traceability in Laboratory Medicine.
The study used 58 specimens from different patient categories. Each specimen was measured in triplicate (ID-LC-MS/MS) and quadruplicate (ID-GC-MS) in independent runs.
The testosterone concentrations by ID-GC-MS were 0.2-4.4 nmol/L (women), 0.2-2.0 nmol/L (hypogonadal man), and 10.1-31.3 nmol/L (normogonadal men). For ID-GC-MS, the CV was nearly constant, with a median of 1.0%; for ID-LC-MS/MS, it was concentration-dependent, with a median of up to 8%. Weighted Deming regression gave mean slopes, intercepts, and correlation coefficients of 0.90-1.11, -0.055-0.013 nmol/L, and 0.993-0.997, respectively. The % difference plot showed between 7% and 26% of the results outside a total error limit of 14%, with median deviations from ID-GC-MS between -9.6 and 0.4%.
This study demonstrated fairly good accuracy and standardization of the tested ID-LC-MS/MS procedures. Performance differences between procedures were evident in some instances, due to improper calibration and between-run calibration control. This emphasizes the need for thorough validation, including traceability, of new ID-LC-MS/MS procedures.
We compared the efficacy and safety of the gonadotropin-releasing hormone analogue, leuprolide (1 mg subcutaneously daily), with diethylstilbestrol (DES, 3 mg by mouth daily) in patients with prostate cancer and distant metastases (Stage D2) who had not previously received systemic treatment. Initial therapy (leuprolide or DES) was continued for as long as an objective response was noted; crossover to the alternative arm occurred at the time of disease progression or intolerable adverse reactions. Ninety-eight patients were randomly assigned to leuprolide, and 101 to DES. Suppression of testosterone and dihydrotestosterone and decreases in acid phosphatase were comparable in the two groups. Patients receiving DES experienced more frequent painful gynecomastia (P < 0.00001), nausea and vomiting (P = 0.02), edema (P = 0.008), and thromboembolism (P = 0.065) than those receiving leuprolide. The leuprolide group reported more 'hot flashes' (P = 0.00001). Overall, 86 per cent of the leuprolide group had an objective response (complete response, 1 per cent; partial response, 37 per cent; stable disease, 48 per cent), as compared with 85 per cent of the DES group (complete, 2 per cent; partial, 44 per cent; stable, 39 per cent). Actual survival rates at one year were 87 per cent for the leuprolide group and 78 per cent for the DES group (P = 0.17). We conclude that leuprolide offers an important alternative treatment that is therapeutically equivalent to and causes fewer side effects than DES for the initial systemic management of metastatic prostate cancer.
There are currently no definitions regarding “Optimal testosterone control in Prostate Cancer”. Therefore an Expert Consensus Meeting (May 22 2005, San Antonio, USA) and an expert consultation at a Discussion Forum during the 6th International Consultation on New Developments in Prostate Cancer and Prostate Diseases (June 25 2005, Paris, France), have been organised to discuss definitions regarding “Optimal testosterone control in Prostate Cancer”.The experts attending the Expert Consensus Meeting received background information based on recently published data and the predefined definitions and/or recommendations that needed to be discussed. During this meeting, the experts agreed that the term “castration” is misleading in case of luteinising hormone releasing hormone (LHRH) agonists, as castration stands for “surgical removal of the testes”, by bilateral orchiectomy. The experts believe that bilateral orchiectomy should be used as a benchmark for introducing the appropriate testosterone level that needs to be achieved with LHRH agonists. As most patients will achieve and maintain a testosterone level of ≤20ng/dL after bilateral orchiectomy, the experts agreed that this level should be used for defining chemical castration. Furthermore, the experts agreed that a testosterone rise from nadir above 50ng/dL could be considered as clinically relevant and could have implications on treatment.In order to reflect previous agreements with a larger group of experts in the field, questions regarding “Optimal testosterone control in Prostate Cancer” were asked to the delegates of the Discussion Forum using an interactive voting system. Before the interactive voting session, the currently published data were presented to the audience. Similar to the experts, the delegates also indicated that achieving “the lowest testosterone level possible” is their main goal of hormone therapy. 64% of the delegates agreed that they would consider a castrate level of below or equal to 20ng/dL to be optimal.
A method is described for the estimation of free testosterone in human plasma. The mean value for normal men was 0.56 μg per 100 ml, for normal women 0.12 μg, for hirsute women with polycystic ovaries 0.33 μg, for virilized women with polycystic ovaries 0.49 μg. Both wedge resection and prednisone treatment significantly decreased the free plasma testosterone values.
We report preliminary results for the first 164 patients enrolled in a multicenter studycomparing the endocrine effects, efficacy, and safety of 3.6 mg of goserelin acetate (Zoladex) and orchiectomy in patients with Stage D2 prostate cancer. Eighty-one patients were randomly allocated to receive Zoladex and 83 to orchiectomy. The median follow-up time for all patients was two hundred ten days. Median serum levels of testosterone were reduced to castrate levels (< 50 ng/dL) within four weeks in both groups and remained suppressed for up to sixty weeks. An objective response according to modified criteria of the National Prostatic Cancer Project was observed in 81 percent and 78 percent of patients in the Zoladex and orchiectomy groups, respectively. There were no statistically significant differences between treatment groups in the distributions of time to treatment failure or time to disease progression. The most commonly reported adverse events in both treatment groups were hot flashes, cancer-related pain, unspecified pain, and urinary symptoms. These results suggest that Zoladex may offer an alternative to orchiectomy in the treatment of advanced prostate cancer.
What's known on the subject? and What does the study add?
The male steroid hormone metabolism is an important target in the treatment of prostatic diseases. However, present literature is inconsistent about intraprostatic concentrations of steroid hormones and the role of intraprostatic steroid hormones in the arise and the course of prostatic disease is yet to be determined.
Part I of this two-piece reviews the different methods of steroid hormone measurement and gives an overview of steroid hormone concentrations in normal and diseased prostatic tissue. More accurate methods of measurement and increased knowledge of androgenic steroid hormonal pathways of the prostate could lead to better treatment of prostatic diseases.
Owing to inconsistencies and methodological differences, the present peer-reviewed literature lacks conclusive data on the intraprostatic levels of androgens, in particular dihydrotestosterone (DHT), in untreated benign prostatic hyperplasia (BPH) and prostate cancer. To date, no difference has been shown between DHT concentrations in normal prostatic tissue and BPH, and nor has a difference been shown in DHT concentrations between the histologically distinct regions of the prostate. Recent literature has also failed to show a consistent difference in androgen level between BPH and prostate cancer. The role of intraprostatic DHT in the pathogenesis of BPH and in the initiation and progression of prostate cancer thus remains to be established. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels may lead to more optimized and more personalized forms of treatment, and probably new therapeutic targets as well.
Recent data has shown that prostate cancer (PCA) cells are capable of producing testosterone directly from cholesterol, which may contribute to the development of castration resistance. While up-regulation of steroidogenic enzymes has been previously described during castration-resistant prostate cancer (CRPC) progression, regulation of this process is poorly defined. These data examine the role of luteinizing hormone (LH) in the regulation of steroidogenic machinery in PCA cells.
PCA cell lines LNCaP, C4-2B, and 22RV1 were exposed to LH. Gene expression was quantified using real-time PCR and protein expression was characterized with standard Western blot analysis. Steroid analysis was performed using radioimmunoassay (RIA). Cell viability was measured using an MTS viability assay.
Androgen-sensitive (LNCaP) and -independent PCA cells (C4-2B and 22RV1) express both mRNA and protein for LH and LH receptor (LHR). Exposure of these cells to LH for 4 hr increased the expression of several steroidogenic genes. Exposure for 10 days resulted in the increase of additional genes. At both time points, the upregulation of these genes was dose-dependent. This was mirrored by an increase in the expression of several key steroidogenic enzymes, including StAR, CYB5B, CYP11A, and 3βHSD. LH stimulated the production of progesterone and testosterone in LNCaP cells as measured by RIA. We have also demonstrated that treatment of LNCaP cells with LH enhanced their viability.
Our data show that LH-mediated activation of LHR significantly up-regulates the expression of genes and enzymes required for steroidogenesis and increases steroid production in PCA cells.
Our aim is to present a summary of the 2010 version of the European Association of Urology (EAU) guidelines on the treatment of advanced, relapsing, and castration-resistant prostate cancer (CRPC).
The working panel performed a literature review of the new data emerging from 2007 to 2010. The guidelines were updated, and the levels of evidence (LEs) and/or grades of recommendation (GR) were added to the text based on a systematic review of the literature, which included a search of online databases and bibliographic reviews.
Luteinising hormone-releasing hormone (LHRH) agonists are the standard of care in metastatic prostate cancer (PCa). Although LHRH antagonists decrease testosterone without any testosterone surge, their clinical benefit remains to be determined. Complete androgen blockade has a small survival benefit of about 5%. Intermittent androgen deprivation (IAD) results in equivalent oncologic efficacy when compared with continuous androgen-deprivation therapy (ADT) in well-selected populations. In locally advanced and metastatic PCa, early ADT does not result in a significant survival advantage when compared with delayed ADT. Relapse after local therapy is defined by prostate-specific antigen (PSA) values >0.2 ng/ml following radical prostatectomy (RP) and >2 ng/ml above the nadir after radiation therapy (RT). Therapy for PSA relapse after RP includes salvage RT at PSA levels <0.5 ng/ml and salvage RP or cryosurgical ablation of the prostate in radiation failures. Endorectal magnetic resonance imaging and (11)C-choline positron emission tomography/computed tomography (CT) are of limited importance if the PSA is <2.5 ng/ml; bone scans and CT can be omitted unless PSA is >20 ng/ml. Follow-up after ADT should include screening for the metabolic syndrome and an analysis of PSA and testosterone levels. Treatment of castration-resistant prostate cancer (CRPC) includes second-line hormonal therapy, novel agents, and chemotherapy with docetaxel at 75 mg/m(2) every 3 wk. Cabazitaxel as a second-line therapy for relapse after docetaxel might become a future option. Zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications.
The knowledge in the field of advanced, metastatic, and CRPC is rapidly changing. These EAU guidelines on PCa summarise the most recent findings and put them into clinical practice. A full version is available at the EAU office or online at www.uroweb.org.
What’s known on the subject? and What does the study add?
Luteinizing hormone-releasing hormone analogues are a cornerstone in the management of many clinical situations in prostate cancer patients. The multiplicity of drugs make it difficult to decide which is the best drug to prescribe to each patient. Whether or not the different luteinizing hormone-releasing hormone analogues belong to the same drug class is only merely supposed.
This study adds a systematic review of the literature in order to determine whether or not the luteinizing hormone-releasing hormone analogues available for prescription belong to the same drug class (same family, similar chemical structure, mechanism of action, and efficacy). The current evidence available is not enough to support a presumed drug class effect of the various analogues in the treatment of prostate carcinoma.
• To study whether luteinizing hormone-releasing hormone (LHRH) analogues are agents of the same pharmacological class, i.e. whether they have the same clinical effect, using an evidence-based medicine approach.
• We reviewed the evidence on the alleged ‘drug class effect’ among analogues and the existing bibliographic support for their use in various medical indications. We used PubMed as the main search source. Evidence level and degree of recommendation were assigned to each conclusion based on the ‘Scottish Intercollegiate Guidelines Network’.
• There are no studies designed to answer the question of class effect between LHRH analogues or agonists. Reviews and meta-analyses have been performed on many other issues related to therapeutic management either with analogues alone, or in combination with radiation therapy and surgery.
• Direct comparisons do not allow definitive conclusions to be reached. Indirect evidence is obtained from randomized studies comparing the different LHRH analogues with other treatments used to obtain androgen deprivation. Other issues related to pharmacokinetics and pharmacodynamics that can support either the existence or non-existence of class effect were evaluated.
• The current available evidence is not enough to support a presumed class effect of the drug among the different analogues in the treatment of prostate carcinoma in its various clinical situations.
Serum testosterone measurement has no widely accepted place in the management of patients with prostate cancer (PCa). However, several potential clinical applications of serum testosterone determination can be envisaged.
To review the role of testosterone and the androgen axis in the natural history of PCa and evaluate the evidence for the clinical application of serum testosterone measurement in patient screening, diagnosis, and management.
A Medline search retrieved original research and review articles relating to the androgen axis in PCa and the use of testosterone measurement for (1) assessing PCa risk in the general population, (2) adding to the specificity of prostate-specific antigen (PSA) testing, (3) determining tumour aggressiveness, (4) assessing the efficacy of androgen-deprivation therapy (ADT), and (5) optimising the scheduling of intermittent ADT. Relevant data were reviewed during a roundtable discussion, and consensus recommendations were agreed.
A body of data implicates the androgen axis in PCa throughout its natural history. Based on current evidence, serum testosterone measurement cannot be recommended for determining PCa risk, increasing specificity of PSA testing, or assessing tumour aggressiveness. In contrast, for patients receiving ADT, there is a clear rationale for serum testosterone monitoring to ensure that castration levels are achieved. Practical recommendations for testosterone measurement during ADT are outlined. If PSA is rising while on ADT, castration levels of serum testosterone must be demonstrated before hormonal independence can be assumed. Serum testosterone levels might be considered an additional trigger for therapy reinitiation in intermittent ADT schedules. Finally, future prospective studies should further evaluate the potential relevance of testosterone measurement as an independent assessment of prognosis and treatment decision in different disease stages.
As a therapeutic target, serum testosterone levels should be monitored to verify response to ADT and confirm suspected castration independence.
Differentiation between subtle changes in low serum testosterone concentrations, common in women and children, is not possible with current commercially available assays. The objectives of the study were to develop a method based on stable isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) with adequate sensitivity and specificity and to investigate the applicability of this assay in serum samples from pre- and postmenopausal women.
For 16 women, testosterone levels were measured in blood samples drawn two years before and after physiological menopause, and for eight women in samples drawn before and after bilateral oophorectomy. Testosterone was extracted from serum, derivatized and analysed on an LC-MS/MS.
The developed ID-LC-MS/MS method allowed for specific and reproducible measurement of testosterone. Comparison with stable isotope dilution-gas chromatography coupled to mass spectrometry detection by Deming regression analysis gave a slope of 1.025 and an intercept of 0.055 nmol/L (r = 0.9998). A significant decrease was found in testosterone concentrations before and after bilateral oophorectomy (P = 0.02), whereas no significant difference was found before and after natural menopause (P = 0.4).
The ID-LC-MS/MS assay measures serum testosterone with acceptable accuracy and is useful in female samples, supporting the conclusion that the postmenopausal ovary contributes to circulating testosterone. To our knowledge, our analytical method compares favourably to similar published methods in terms of sensitivity. The sensitivity and specificity of this method comply with the reference method for measurement of testosterone in serum samples of women, children and men suffering from hypogonadism and can also be used for men with testosterone in the reference range.
To determine if the testosterone level achieved with androgen-deprivation therapy (ADT) is directly related to survival and risk of death in men with metastatic prostate cancer, as agonistic analogues of luteinizing hormone-releasing hormones (LHRH) are indicated for palliative treatment of these patients, but there is no consensus about the utility of serum testosterone measurements during the follow-up, and their possible prognostic value.
We retrospectively reviewed 129 consecutive patients with a histological diagnosis of metastatic bony-only prostate cancer and previously untreated with ADT. They were treated with 3 months of goserelin. Testosterone and prostate-specific antigen (PSA) levels were measured in all patients every 3 months for the duration of the follow-up. The following variables were recorded: age, stage, Gleason score, basal PSA level, basal testosterone level, PSA nadir, time to PSA nadir, testosterone after 6 months, testosterone nadir and time to testosterone nadir. Data were analysed using Cox's proportional hazards models, with the primary endpoint being cancer-specific survival.
The mean (SD) basal PSA level was 185.8 (344.1) ng/mL, and the mean nadir PSA level 2.7 (8.6) ng/mL. The mean testosterone levels at baseline, 6 months and the nadir were 440 (200), 40 (40) and 21 (15) ng/dL. With a mean follow-up of 47.5 (29.7) months, 71 patients were dead (55%) and 78 were alive (45%) at the time of analysis. Statistical analysis using Cox's model showed that in these patients the risk of death was directly correlated not only to Gleason score (P < 0.01) and to the 6-month PSA level (P < 0.01), but also to the 6-month serum testosterone level (hazard ratio 1.32, P < 0.05).
These results suggest a direct correlation between the risk of death and testosterone levels achieved during ADT. Based on the present results, lowering the testosterone level as much as possible should be the goal of ADT in patients with metastatic prostate cancer, as this might affect patient survival.
Because it is well known that prostatic cancer is dependent on testosterone, and that dihydrotestosterone is the active mediator of the androgen action in the prostatic cell, we studied serum concentrations of testosterone and dihydrotestosterone in 84 patients with prostatic cancer, 40 of whom were treated by orchidectomy, and 44 who were not treated. There was a significant correlation between testosterone and dihydrotestosterone concentrations in the untreated group, but no correlation among the patients treated by orchidectomy. The results indicate that the effectiveness of orchidectomy as androgen withdrawal treatment in prostatic cancer should be assessed by measurement of both dihydrotestosterone and testosterone concentrations.
We report preliminary results for the first 164 patients enrolled in a multicenter study comparing the endocrine effects, efficacy, and safety of 3.6 mg of goserelin acetate (Zoladex) and orchiectomy in patients with Stage D2 prostate cancer. Eighty-one patients were randomly allocated to receive Zoladex and 83 to orchiectomy. The median follow-up time for all patients was two hundred ten days. Median serum levels of testosterone were reduced to castrate levels (less than 50 ng/dL) within four weeks in both groups and remained suppressed for up to sixty weeks. An objective response according to modified criteria of the National Prostatic Cancer Project was observed in 81 percent and 78 percent of patients in the Zoladex and orchiectomy groups, respectively. There were no statistically significant differences between treatment groups in the distributions of time to treatment failure or time to disease progression. The most commonly reported adverse events in both treatment groups were hot flashes, cancer-related pain, unspecified pain, and urinary symptoms. These results suggest that Zoladex may offer an alternative to orchiectomy in the treatment of advanced prostate cancer.
Between November 1983 and February 1986, 358 patients with previously untreated metastatic prostatic carcinoma entered a multicentre, randomised trial in the United Kingdom and the Republic of Ireland, in which the LHRH analogue Zoladex (ICI Pharmaceuticals PLC), administered subcutaneously every 28 days, was compared with orchiectomy. Both treatments were equally effective in lowering serum testosterone concentrations to within the surgically castrate range and this was accompanied by equivalent subjective and objective response rates and times to treatment failure. At a median follow-up of 2 years there was no difference in overall survival, confirming that Zoladex is an effective medical alternative to orchiectomy in patients with metastatic disease.
Two multicenter, open, randomized phase III clinical trials were conducted in the United Kingdom to compare the effectiveness and safety of the depot formulation of the luteinizing hormone-releasing hormone (LHRH) agonist goserelin (Zoladex, ICI Pharma, Wilmington, Delaware), 3.6 mg sc/28 d, with orchiectomy and with diethylstilbestrol (DES), 1 mg tid, in the treatment of advanced prostatic cancer. In the Zoladex versus orchiectomy trial, there was no significant difference between the treatment groups with regard to subjective and objective responses (British Prostate Group criteria), endocrine responses, clinical effects and side effects, time to treatment failure and death, or survival after similar median follow-up periods. It was concluded that depot Zoladex had behaved as a truly medical alternative to orchiectomy. In the Zoladex versus DES trial, subjective and objective responses (British Prostate Group and National Prostatic Cancer Project criteria), response duration and survival were similar. However, there was a more rapid response to treatment in the depot Zoladex group. Side effects from Zoladex such as flare symptoms during the initial stages of treatment required no discontinuation of therapy; in contrast, 15 percent of patients receiving DES required cessation of therapy during the first three months because of side effects. It was concluded that depot Zoladex was superior to DES in its attainment of an early objective response and in its absence of side effects, and that Zoladex was comparable with DES in terms of response rates and survival.
Plasma testosterone has been estimated by radioimmunoassay in 109 patients with prostatic carcinoma and 18 men of similar age with benign prostatic hyperplasia.
Stilboestrol 1 mg 3 times daily, Premarin 2.5 mg 3 times daily, Honvan 100 mg 3 times daily or ethinyloestradiol 0–05 mg twice daily are as effective as large doses of stilboestrol or as orchidectomy in producing a profound and sustained fall in plasma testosterone, but stilboestrol 1 mg daily is not uniformly effective.
TACE has no measurable effect on the plasma testosterone.
No rise in plasma testosterone is noted in relapse, but pituitary ablation by implantation of yttrium-90 produces a fall in plasma testosterone greater than that achieved by oestrogens alone.
This article has no abstract; the first 100 words appear below.
TESTOSTERONE is the most potent of naturally occurring androgens, but attempts to measure testosterone in human peripheral venous plasma by standard chemical technics have generally been unsuccessful.¹ This lack of success has been thought to be due to low circulating concentration of testosterone. The concentration of the free hormone in peripheral plasma appears to reflect more nearly the quantity available for tissue activity than the amount of hormone in urine or other body fluids. The majority of the 17-ketosteroids found in urine are the metabolic products of other less potent androgens than testosterone, and their measurement is a nearly useless . . .
*From the Research Service, Veterans Administration Hospital, and the Department of Medicine, Vanderbilt University School of Medicine.
Presented, in part, before the Southern Society for Clinical Investigation, New Orleans, January 22, 1965.
We are indebted to Dr. Harry S. Shelley, chief, Urology Service, Nashville Veterans Administration Hospital, for allowing us to study patients under his care.
Source Information
NASHVILLE, TENNESSEE
† Clinical investigator, Veterans Administration Hospital; assistant professor of medicine, Vanderbilt University School of Medicine.
‡ Biochemist, Veterans Administration Hospital.
To compare the efficacy and safety of goserelin and orchiectomy in patients with stage D2 prostate cancer.
A randomized, open, multicenter study was conducted in 283 patients. Patients were allocated to goserelin, 3.6 mg every 28 days or to orchiectomy. Study end points were endocrine response, objective response, time to treatment failure, survival, and tolerability. Objective response was based on modified criteria of the National Prostate Cancer Project.
Serum testosterone decreased from baseline to castrate levels by week 4 in each group and remained below castrate levels thereafter. Acid phosphatase and alkaline phosphatase concentrations also decreased in each group. The goserelin and orchiectomy groups had similar results for objective response (82% versus 77%) and had similar medial times to treatment failure (52 versus 53 weeks) and survival (119 versus 136 weeks). No significant interactions between treatments and prognostic factors were observed. Adjusting for baseline testosterone concentration had no effect on survival outcome. Race had no influence on outcome or efficacy end points. Common adverse events in both groups were pain, hot flushes, and lower urinary tract symptoms.
Goserelin is well tolerated and as effective as orchiectomy in patients with Stage D2 prostate cancer.
We report the failure to achieve a castrate level of testosterone associated with 3-month depot luteinizing hormone releasing hormone (LH-RH) agonist therapy, which to our knowledge is a previously unrecognized outcome.
We prospectively enrolled in our study 38 men with prostate cancer on 3-month depot LH-RH agonist therapy. We monitored total serum testosterone and prostate specific antigen every 28 days beginning 90 days after the last depot LH-RH agonist injection. Data were analyzed with castrate testosterone defined as less than 50 and 20 ng./dl. or less.
Using the 50 and 20 ng./dl. definitions of castrate testosterone 2 (5%) and 5 (13%) of the 38 men, respectively, failed to achieve castrate testosterone. A patient with a nadir testosterone of 70 ng./dl. subsequently underwent orchiectomy and testosterone decreased to 10 ng./dl. thereafter.
A small but potentially important subgroup of men on depot LH-RH agonist therapy fail to achieve a castrate level of testosterone. Our findings support monitoring testicular response when LH-RH agonist therapy is initiated.
Based on methods introduced in the late 1960s and no longer used, serum testosterone level in men after surgical castration was reported to be 50 ng/dL or less. Radioimmunoassay and, subsequently, chemiluminescent methods have supplanted the early analytic methods because of their improved accuracy and ease of testing. The purpose of this study was to define the castrate testosterone level in the era of chemiluminescent testing.
After bilateral orchiectomy, serum testosterone (total) levels were measured prospectively in 35 prostate cancer patients.
The median testosterone value in this patient cohort was 15 ng/dL (0.5 nmol/L; 95% confidence interval 12 to 17 ng/dL).
In a contemporary series, castrate testosterone should be defined as less than 20 ng/dL (0.7 nmol/L). The important biologic and economic implications are discussed.
The long duration of phase III clinical trials of overall survival (OS) slows down the treatment-development process. It could be shortened by using surrogate end points. Prostate-specific antigen (PSA) is the most studied biomarker in prostate cancer (PCa). This study attempts to validate PSA end points as surrogates for OS in advanced PCa.
Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation. PSA response, PSA normalization, time to PSA progression, and longitudinal PSA measurements were considered.
The known association between PSA and OS at the individual patient level was confirmed. The association between the effect of intervention on any PSA end point and on OS was generally low (determination coefficient, < 0.69).
It is a common misconception that high correlation between biomarkers and true end point justify the use of the former as surrogates. To statistically validate surrogate end points, a high correlation between the treatment effects on the surrogate and true end point needs to be established across groups of patients treated with two alternative interventions. The levels of association observed in this study indicate that the effect of hormonal treatment on OS cannot be predicted with a high degree of precision from observed treatment effects on PSA end points, and thus statistical validity is unproven. In practice, non-null treatment effects on OS can be predicted only from precisely estimated large effects on time to PSA progression (TTPP; hazard ratio, < 0.50).
In a cross-sectional, retrospective, non-randomised study to investigate the possibility that some patients treated with luteinizing hormone releasing hormone analogues (LHRH analogues) fail to reach castration levels of serum testosterone.
40 patients treated with a 3-monthly formulation of leuprolide acetate and continuous use of an oral antiandrogen ("Leu group") and 25 patients treated with a 3-monthly formulation of goserelin acetate and an oral antiandrogen for one month ("Gos group") were identified from our hospital's registry. Serum testosterone was measured during treatment with the respective LHRH-analogue and compared between the two groups. In the Leu group, serum testosterone was measured during week 11 or 12 of treatment. In the Gos group, serum testosterone was assessed during week 23 or 24.
Four patients (10%) treated with leuprolide acetate failed to reach the castration level of serum testosterone after treatment with one injection of a three-monthly formulation of leuprolide acetate. All patients treated with goserelin acetate achieved the castration level.
Although the overwhelming majority of prostate cancer patients during treatment of LHRH analogue achieve serum testosterone values within the castration range, individual patients may fail to reach this therapeutic goal, probably more often during treatment with leuprolide acetate than with goserelin acetate.
We determined the testosterone castration level with clinical relevance in patients with prostate cancer on continuous androgen deprivation therapy. Secondary objectives were to analyze the role of associated bicalutamide in breakthrough increases of serum testosterone in these patients and the possible benefit of maximal androgen blockade.
Serum testosterone was determined 3 times (in 6 months) in 73 patients with nonmetastatic prostate cancer treated with medical castration, 28 (38.4%) of whom also received bicalutamide (maximal androgen blockade). During a mean followup of 51 months (range 12 to 240) 41 (67.1%) events of androgen independent progression were identified, and correlated with breakthrough testosterone increases of 50 ng/dl (classic level) and 20 ng/dl (surgical castration level).
Testosterone was less than 20 ng/dl in all determinations in 32 patients (43.6%). Breakthrough increases between 20 and 50 ng/dl were observed in 23 patients (31.5%), and increases greater than 50 ng/dl were observed in the remaining 18 (24.7%). The lowest testosterone level with a significant impact on survival free of androgen independent progression was 32 ng/dl. Mean survival free of androgen independent progression in patients with breakthrough increases greater than 32 ng/dl was 88 months (95% CI 55-121) while it was 137 months (95% CI 104-170) in those without breakthrough increases (p <0.03). Patients on maximal androgen blockade had an incidence of testosterone increase similar to those receiving monotherapy. However, maximal androgen blockade provided a significantly longer survival free of androgen independent progression in those with breakthrough increases greater than 50 ng/dl.
In the current report the lowest testosterone castration level with clinical relevance in medically castrated patients with prostate cancer was 32 ng/dl. Breakthrough increases greater than this threshold predicted a lower survival free of androgen independent progression. Maximal androgen blockade might benefit medically castrated cases of prostate cancer with breakthrough increases of more than 50 ng/dl.
Is prostate-specific antigen a valid surrogate end point for survival in hormonally treated patients with metastatic prostate cancer?
- Collette