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Abstract: Objective: This study was performed to elucidate the mechanism of high bone turnover during androgen deprivation therapy (ADT) in terms of osteogenic endocrine activity by testosterone, adrenal androgens, and insulin-like growth factor-1 (IGF-I), and to identify markers reflecting the bone mineral density (BMD) during ADT. Design: BMD and samples of blood and urine were studied before and after 6months of ADT in 70 patients with localized prostate cancer. Results: Before ADT, serum free-testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and IGF-I levels were correlated with BMD (rs=0.344, p=0.004; rs=0.264, p=0.027; rs=0.329, p=0.005; rs=0.300, p=0.012, respectively). The serum IGF-I level was independently correlated with the pretreatment BMD (Multivariate p=0.001). These relationships disappeared after ADT (p=0.519, 0.316, 0.116, and 0.597, respectively). After ADT, serum levels of free-testosterone decreased (7.9 to 0.2pg/mL), and DHEA-S and androstenedione were also reduced (3.6 to 2.3μmol/L and 5.6 to 2.9nmol/L, respectively) (p<0.001 in all). In contrast, IGF-I levels were elevated after ADT by 11.6% (19.9 to 22.3nmol/L, p<0.001). Delta-values of IGF-I (post- minus pretreatment levels, mean: +2.2, ranged between −7.1 and +15.3) were inversely correlated with the pretreatment (rs=−0.333 p=0.005) and post-treatment (rs=−0.408, p=0.001) BMD. After ADT, the serum IGF-I level was closely correlated with the serum level of the bone formation marker bone-specific alkaline phosphatase (BAP) (rs=0.328, p=0.006), and delta-IGF-I and delta-BAP showed a close positive correlation (rs=0.388, p=0.001). The post-treatment BMD was correlated only with the urine deoxypyridinoline (DPD) concentration (rs=−0.302, p=0.024) among the bone formation/resorption markers including serum/urine N-telopeptide. Conclusions: Serum IGF-I levels increased during ADT in men with a low BMD. Coupled with reduced androgen levels, elevated IGF-I levels, which were positively correlated with BAP during ADT, possibly explain the mechanism of ADT-related high bone turnover. The increase of IGF-I is more prominent in men whose BMD is already low at the baseline, and urine DPD might be a marker that reflects BMD during ADT. [Copyright &y& Elsevier]

Abstract: Androgen deprivation therapy (ADT) has remained the main therapeutic option for patients with advanced prostate cancer (PCa) for about 70 years. Several reports and our findings revealed that aggressive PCa can occur under a low dihydrotestosterone (DHT) level environment where the PCa of a low malignancy with high DHT dependency cannot easily occur. Low DHT levels in the prostate with aggressive PCa are probably sufficient to propagate the growth of the tumor, and the prostate with aggressive PCa can produce androgens from the adrenal precursors more autonomously than that with non-aggressive PCa does under the low testosterone environment with testicular suppression. In patients treated with ADT the pituitary-adrenal axis mediated by adrenocorticotropic hormone has a central role in the regulation of androgen synthesis. Several experimental studies have confirmed the potential benefits from the combination of ADT with radiotherapy (RT). A combination of external RT with short-term ADT is recommended based on the results of phase III randomized trials. In contrast, the combination of RT plus 6 months of ADT provides inferior survival as compared with RT plus 3 years of ADT in the treatment of locally advanced PCa. Notably, randomized trials included patients with diverse risk groups treated with older RT modalities, a variety of ADT scheduling and duration and, importantly, suboptimal RT doses. The use of ADT with higher doses of RT or newer RT modalities has to be properly assessed. [Copyright &y& Elsevier]

Abstract: The intracellular androgen metabolism and cell activity in prostate cancer cells with mutated (LNCaP-FGC) or wild-type (VCaP) androgen receptors in the presence of trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, were examined. Trilostane suppressed the intracellular production of androstenedione, testosterone, and dihydrotestosterone from dehydroepiandrosterone in LNCaP-FGC cells. In both LNCaP-FGC and VCaP cell types, the prostate-specific antigen (PSA) levels in media were increased by trilostane alone in a concentration-dependent manner. Both cells pretreated with trilostane showed a dose-dependent decrease in PSA production with bicalutamide (P <0.001). Trilostane should be used with particular concern when treating prostate cancer. [Copyright &y& Elsevier]

Abstract: Fe x Co100–x (x=100, 65, 50at%) epitaxial thin films were prepared on MgO(110) single-crystal substrates heated at 300°C by ultra-high vacuum molecular beam epitaxy. The film structure and the growth mechanism are discussed. FeCo(211) films with bcc structure grow epitaxially on MgO(110) substrates with two types of variants whose orientations are rotated around the film normal by 180° each other for all compositions. Fe x Co100–x film growth follows the Volmer Weber mode. X-ray diffraction analysis indicates the out-of-plane and the in-plane lattice spacings are in agreement with the values of respective bulk Fe x Co100–x crystals with very small errors less than ±0.4%, suggesting the strains in the films are very small. High-resolution cross-sectional transmission electron microscopy shows that periodical misfit dislocations are preferentially introduced in the film at the Fe50Co50/MgO interface along the MgO[11¯0] direction. The presence of such periodical dislocations decreases the large lattice mismatch of about −17% existing at the FeCo/MgO interface along the MgO[11¯0] direction. [Copyright &y& Elsevier]

Objectives: To elucidate the mechanism of blood hemoglobin loss in patients with prostate cancer during androgen deprivation therapy (ADT), and to examine the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis during ADT, which plays an important role in hematopoiesis. Methods: A total of 83 patients with localized prostate cancer, who received ADT, were prospectively studied on the basis of their blood samples at the baseline and after ADT for 6 months. Results: Before ADT, the IGF-1 level was correlated with the red blood cell (RBC) count (Spearman''s rank correlation coefficient analysis [rs]= 0.315, P = .011), hemoglobin (rs = 0.278, P = .018), and mean corpuscular volume (rs = 0.266, P = .020), but such relationships disappeared after ADT. After ADT, the serum IGF-1 level increased compared with that at the baseline (21 ± 6 vs 18 ± 5 nmol/L, respectively, P <.001), but no change was observed in the serum GH level (P = .691). There was no difference between erythropoietin and interleukin-6 concentrations before and after ADT (P = .852 and P = .208, respectively). The hemoglobin concentration and RBC count declined after ADT compared with those before treatment (P <.001 for each). Although the mean corpuscular volume declined after ADT (P = .002), the mean cell hemoglobin was comparable between before and after ADT (P = .676). Conclusions: Despite the unaffected GH, erythropoietin, and interleukin-6 levels, the serum IGF-1 concentration was elevated by ADT. Even with the increased IGF-1 level, the RBC count and hemoglobin concentration declined after ADT. IGF-1 in the bone marrow erythroid progenitor cells might be functionally inactivated during ADT. [Copyright &y& Elsevier]

Androgens are heavily involved in the development of prostate cancer. This article reviews the scenario of the androgen environment and androgen metabolism in the prostate during androgen-deprivation therapy (ADT) in patients with prostate cancer. Ways of altering the intra-prostatic androgen milieu during various androgen-blockade regimens include surgical castration, luteinizing hormone-releasing hormone analogues to block androgen secretion by the testes, anti-androgens, and 5α-reductase inhibitors. The levels of androgen precursors in the blood are different under different ADT regimens, and the androgen levels in the prostate also vary according to the ADT used. This may affect the therapeutic effect of ADT. We therefore discuss the subject of prostatic androgen levels during various androgen-blockade regimens, and we describe the prospects for the future of ADT. [Copyright &y& Elsevier]

Objectives: To clarify the influence of androgen deprivation therapy (ADT) on the volume of the anatomic zones of the prostate and the tissue component of the transition zone.Methods: Thirty patients with prostate cancer arising and localizing in the peripheral zone were enrolled in this study. The volume of anatomic zones was measured using magnetic resonance imaging before and 6 months after ADT (castration and flutamide). Binary images were constructed to analyze the tissue components of the transition zone.Results: The volumes after ADT in the whole prostate, transition zone, and peripheral zone were significantly smaller than the corresponding volumes before ADT (P <0.001). A small correlation was found between the reduction rates of the transition zone after therapy and the stromal rates of the transition zone (rs = 0.375, P = 0.041).Conclusions: The present results revealed that, not only the epithelial region in the transition zone, but also the stromal region, was sensitive to androgen and the volume of the transition zone was reduced during ADT regardless of its histologic components. [Copyright &y& Elsevier]

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 600 ng/dl (17.3-20.8 nmol) down to castration levels. Traditionally, castration was considered to be achieved if testosterone levels were lowered to a threshold of 50 ng/dl (1.73 nmol/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 20 ng/dl (0.69 nmol/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. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the mechanism of the androgen deprivation therapy (ADT)-related decrease in lean body mass (LBM). Materials and Methods: The LBM and blood samples were studied before and after 6 months of ADT in 72 patients with localized prostate cancer. The LBM was assessed using a foot-to-foot bioelectrical impedance analyzer. Results: Before ADT, the LBM correlated with none of the serum sex steroid levels; however, it correlated closely with serum 5α-androstane-3α,17β-diol glucuronide (Spearman''s rank correlation coefficient = 0.409, P = .001) and insulin-like growth factor-1 (IGF-I, Spearman''s rank correlation coefficient = 0.329, P = .005). After ADT, the LBM decreased by 0.9% (P = .036), and the serum testosterone and dihydrotestosterone had decreased by 96.8% and 94.3%, respectively (P <.001 for both), and the IGF-I had increased by 11.6% (from 19.9 to 22.2 nmol/L, P = .001). The serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D] levels decreased after ADT by 9.8% (from 66.2 to 59.7 pg/mL, P = .008), and the post-treatment LBM correlated inversely with 1,25(OH)2D (Spearman''s rank correlation coefficient = −0.343, P = .003). The post-treatment LBM was dissociated with 5α-androstane-3α,17β-diol glucuronide and IGF-I. The pretreatment and post-treatment LBMs both correlated inversely with serum sex hormone-binding globulin (P = .024 and P = .016, respectively). Conclusion: The deficiency in androgen levels was suggested to be a link to the ADT-related decrease in LBM; the androgen metabolite 5α-androstane-3α,17β-diol glucuronide has a potential value for assessing the LBM in untreated men. IGF-I also promotes muscle building and is positively regulated during ADT. Sex hormone-binding globulin possibly accelerates the ADT-related decrease in LBM. Although the mechanism for the decrease in 1,25(OH)2D and its inverse correlation with LBM during ADT is unclear, 1,25(OH)2D might be a biomarker reflecting the ADT-related decrease in LBM. [Copyright &y& Elsevier]

Abstract: Background: Luteinizing hormone (LH) during androgen-deprivation therapy (ADT) with gonadotropin-releasing hormone analogues (GnRHa) has been thought to be biologically inactive, and the regulation of LH during ADT with GnRHa is thus unknown. Insulin-like growth factor-1 (IGF-1) is involved in the regulation of cell proliferation and differentiation, and IGF-1 production in the liver is dependent on growth hormone (GH) secretion from the anterior pituitary. Despite the presence of IGF-1 receptors in the gonadotroph, associations between the GH/IGF-1 and pituitary-gonadal axes, e.g., whether IGF-1 elicits the LH secretion, remain unclear. Methods: Seventy-one patients with localized prostate cancer, who received ADT with GnRHa, were prospectively studied based on their blood samples before treatment and after ADT for 6 months. We employed highly sensitive assays for measurement of serum testosterone (electrochemiluminescence immunoassay), GH/IGF-1 (radioimmunoassay), adrenocorticotropic hormone (ACTH: immunoradiometric assay), LH (chemiluminescent immunoassay), and dehydroepiandrosterone sulfate (DHEA-S: chemiluminescent enzyme immunoassay). Results: No correlation was noted between the pretreatment LH and IGF-1 levels; after ADT, the serum LH level was closely correlated with the IGF-1 concentration [Spearman''s correlation coefficient (rs) = 0.370, P = 0.001]. The serum levels of androgens and gonadotropins reduced following ADT (P < 0.001 in all). The serum IGF-1 level increased (22 ± 6 nmol/L) compared with that at the baseline (19 ± 5 nmol/L) (P < 0.001), but no change was observed in the serum GH concentration between before and after ADT (1.4 ± 2.3 vs. 0.9 ± 0.9 μg/L, respectively, P = 0.691). The serum testosterone level was not correlated with the LH level either before or after ADT. The testosterone and DHEA-S levels after ADT were correlated with ACTH concentration (rs = 0.367, P = 0.002 and rs = 0.354, P = 0.002, respectively). We did not identify any correlations between the serum IGF-1 concentration and Gleason score, PSA value, or androgen levels. Conclusions: During ADT with GnRHa, IGF-1 possibly promotes LH production, although its role is unclear. Associations among pituitary-gonadal, pituitary-adrenal, and GH/IGF-1 axes represented by IGF-1-mediated LH secretion and ACTH-mediated androgen synthesis are of interest, since both prostate epithelium proliferation and male anabolic activity are involved in these 3 axes. Assessment of oncologic outcomes is warranted for their significance in patients with prostate cancer. [Copyright &y& Elsevier]

Abstract: Background: The kinetics and reproducibility of serum prostate-specific antigen (PSA) following extended multisite biopsies are unknown. The aim of this study was to examine the kinetics of hematogenous leakage of PSA molecules by comparing the postintervention PSA manner among extended biopsies, transurethral resection of the prostate (TURP) and biopsy plus TURP. Methods: Total and free PSA values were examined before and sequentially after intervention (at 1 hour, 24 hours, 2 days, 14 days, and 28 days), in patients who underwent 14-core prostate biopsy (Biopsy, n = 53), TURP (TURP, n = 21), or prostate biopsy plus TURP (Biopsy+TURP, n = 18). Results: Ten patients in the Biopsy group were histologically diagnosed as having prostate cancer, and all other patients were diagnosed with non-malignant disorders. One hour after intervention, the increase in total PSA in the Biopsy group (mean 19.58 ± 24.78-fold) and Biopsy+TURP group (mean 14.00 ± 10.52-fold) was higher than that of the TURP group (mean 6.189 ± 7.567-fold) (P = 0.0207 and 0.0119, respectively). The increase in total PSA in the Biopsy+TURP group was not different from that of the Biopsy group. The increase in free PSA in the Biopsy group (mean 36.52 ± 21.18-fold or more) was greater than that of the TURP group (mean 15.57 ± 18.17-fold) (P = 0.0002 or less). Both total and free PSA values in the Biopsy group recovered to the initial levels 28 days after intervention (P = 0.380 and P = 0.0873, respectively). The course of both total and free PSA values in the Biopsy group was not different between prostate cancer and non-malignant disorders. Conclusions: Extended multisite biopsies caused marked elevation of both total and free PSA compared with ordinary sextant protocol or TURP, and they reduced to the preoperative levels in about 4 weeks. The postintervention increase of PSA and its manner of recovery were comparable between the Biopsy and Biopsy+TURP groups, suggesting that the hematogenous leakage of PSA by biopsies occurs in an early phase just after biopsy and rapidly reduces also in the early phase. [Copyright &y& Elsevier]