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Early effects of androgen deprivation on bone and mineral homeostasis in adult men: a prospective cohort study.
Khalil, R, Antonio, L, Laurent, MR, David, K, Kim, NR, Evenepoel, P, Eisenhauer, A, Heuser, A, Cavalier, E, Khosla, S, et al
European journal of endocrinology. 2020;(2):181-189
Abstract
OBJECTIVE Long-term androgen deprivation therapy (ADT) negatively influences bone. The short-term effects on bone and mineral homeostasis are less known. Therefore, we aimed to investigate the early effects of ADT on calcium/phosphate homeostasis and bone turnover. DESIGN Prospective cohort study. METHODS Eugonadal adult, male sex offenders, who were referred for ADT to the endocrine outpatient clinic, received cyproterone acetate. Changes in blood markers of calcium/phosphate homeostasis and bone turnover between baseline and first follow-up visit were studied. RESULTS Of 26 screened patients, 17 were included. The median age was 44 (range 20-75) years. The median time interval between baseline and first follow-up was 13 (6-27) weeks. Compared to baseline, an 81% decrease was observed for median total testosterone (to 3.4 nmol/L (0.4-12.2); P < 0.0001) and free testosterone (to 0.06 nmol/L (0.01-0.18); P < 0.0001). Median total estradiol decreased by 71% (to 17.6 pmol/L (4.7-35.6); P < 0.0001). Increased serum calcium (P < 0.0001) and phosphate (P = 0.0016) was observed, paralleled by decreased PTH (P = 0.0156) and 1,25-dihydroxyvitamin D3 (P = 0.0134). The stable calcium isotope ratio (δ44/42Ca) decreased (P = 0.0458), indicating net calcium loss from bone. Bone-specific alkaline phosphatase and osteocalcin decreased (P < 0.0001 and P = 0.0056, respectively), periostin tended to decrease (P = 0.0500), whereas sclerostin increased (P < 0.0001), indicating suppressed bone formation. Serum bone resorption markers (TRAP, CTX) were unaltered. CONCLUSIONS In adult men, calcium release from the skeleton occurs early following sex steroid deprivation, reflecting early bone resorption. The increase of sclerostin and reduction of bone formation markers, without changes in resorption markers, suggests a dominant negative effect on bone formation in the acute phase.
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HSD3B1 and Response to a Nonsteroidal CYP17A1 Inhibitor in Castration-Resistant Prostate Cancer.
Almassi, N, Reichard, C, Li, J, Russell, C, Perry, J, Ryan, CJ, Friedlander, T, Sharifi, N
JAMA oncology. 2018;(4):554-557
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Abstract
IMPORTANCE The HSD3B1 (1245C) germline variant encodes for a gain-of-function missense in 3β-hydroxysteroid dehydrogenase isoenzyme 1 (3βHSD1) that results in increased dihydrotestosterone synthesis from extragonadal precursors and is predictive of more rapid progression to castration-resistant prostate cancer (CRPC). OBJECTIVE To determine whether the HSD3B1 (1245C) genotype is predictive of clinical response to extragonadal androgen ablation with nonsteroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition in men with metastatic CRPC. DESIGN, SETTING, AND PARTICIPANTS An observational study of men with metastatic CRPC treated with ketoconazole between June 1998 and December 2012 was conducted at the University of California, San Francisco. EXPOSURES Extragonadal androgen ablation with the nonsteroidal CYP17A1 inhibitor ketoconazole among men with metastatic CRPC. MAIN OUTCOMES AND MEASURES The primary end points of analysis were duration of ketoconazole therapy and time to disease progression stratified by HSD3B1 genotype. Disease progression was defined as either biochemical or radiographic progression, using the Prostate Cancer Working Group 3 and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 definitions, respectively. Kaplan-Meier analysis was used to estimate time on therapy and time to disease progression. A log-rank test for trend was used to compare outcomes by HSD3B1 genotype. RESULTS A total of 90 men (median [interquartile range] age, 61.5 [55.3-67.0] years) with metastatic CRPC were included in the analysis, with sufficient data to determine duration of ketoconazole therapy and time to disease progression in 88 and 81 patients, respectively. The median duration of therapy increased with the number of inherited HSD3B1 (1245C) variant alleles: 5.0 months (95% CI, 3.4-10.4) for 0 variant alleles; 7.5 months (95% CI, 4.9-19.2) for 1; and 12.3 months (95% CI, 1.8-not reached) for 2 (overall comparison for trend, P = .01). Median progression-free survival also increased with number of HSD3B1 (1245C) variant alleles inherited: 5.4 months (95% CI, 3.7-7.5) for 0 variant alleles; 9.7 months (95% CI, 5.6-32.9) for 1; and 15.2 months (95% CI, 7.8-not reached) for 2 (overall comparison for trend, P = .03). CONCLUSIONS AND RELEVANCE Inheritance of the HSD3B1 (1245C) variant allele, which is a predictive biomarker of resistance to castration, is also a predictive biomarker of sensitivity to extragonadal androgen ablation with a nonsteroidal CYP17A1 inhibitor. These findings signal a possible pathway of treatment stratification for patients with prostate cancer.
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Effect of androgen deprivation therapy on arterial stiffness and serum lipid profile changes in patients with prostate cancer: a prospective study of initial 6-month follow-up.
Oka, R, Utsumi, T, Endo, T, Yano, M, Kamijima, S, Kamiya, N, Shirai, K, Suzuki, H
International journal of clinical oncology. 2016;(2):389-396
Abstract
BACKGROUND To explore arterial stiffness during the administration of androgen deprivation therapy (ADT) in patients with prostate cancer (PCa), a new indicator, the cardio-ankle vascular index (CAVI), and serum lipid profile changes were monitored. METHODS A prospective study assessed the changes in arterial stiffness using the CAVI and clinical laboratory variables among 58 men with prostate cancer treated with ADT for 6 months. Furthermore, patients who had a high risk of developing arterial stiffness after ADT were investigated. RESULTS The whole cohort had no significant increase in arterial stiffness within 6 months after ADT, but 55.2 % of patients had an increased CAVI. Serum levels of total cholesterol, high-density-lipoprotein cholesterol (HDL-C), and low-density-lipoprotein cholesterol (LDL-C) increased significantly at 1 month after the start of ADT and maintained high values thereafter. At baseline, HDL-C was lower and LDL-C and LDL-C/HDL-C were higher in the group with than without an increased CAVI after 6 months of ADT administration. CONCLUSIONS Although the whole cohort did not show a significant change in arterial stiffness with ADT, some patients showed an increased arterial stiffness monitored with the CAVI. The balance between LDL-C and HDL-C, or LDL-C/HDL-C, might have an impact on the development of arterial stiffness after ADT administration. Thus, clinicians might be able to monitor PCa patients who have a high risk of development of arterial stiffness after ADT administration by referring to LDL-C/HDL-C levels.
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The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy.
Morote, J, Gómez-Caamaño, A, Alvarez-Ossorio, JL, Pesqueira, D, Tabernero, A, Gómez Veiga, F, Lorente, JA, Porras, M, Lobato, JJ, Ribal, MJ, et al
The Journal of urology. 2015;(6):1963-9
Abstract
PURPOSE Androgen deprivation therapy may promote the development of the metabolic syndrome in patients with prostate cancer. We assessed the prevalence of the full metabolic syndrome and its components during the first year of androgen deprivation therapy. MATERIALS AND METHODS This observational, multicenter, prospective study included 539 patients with prostate cancer scheduled to receive 3-month depot luteinizing hormone-releasing hormone analogs for more than 12 months. Waist circumference, body mass index, lipid profile, blood pressure and fasting glucose were evaluated at baseline and after 6 and 12 months. The metabolic syndrome was assessed according to NCEP ATP III criteria (2001) and 4 other definitions (WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005). RESULTS At 6 and 12 months after the initiation of androgen deprivation therapy, significant increases were observed in waist circumference, body mass index, fasting glucose, triglycerides, total cholesterol, and high-density and low-density lipoprotein cholesterol. No significant changes in blood pressure 130/85 or greater were detected. A nonsignificant increase of 3.9% in the prevalence of the full metabolic syndrome (ATP III) was observed (22.9% at baseline vs 25.5% and 26.8% at 6 and 12 months, respectively). The prevalence of the metabolic syndrome at baseline varied according to the definition used, ranging from 9.4% (WHO) to 50% (IDF). At 12 months significant increases in prevalence were observed with the WHO (4.1%) and AHA/NHLBI (8.1%) definitions. CONCLUSIONS Androgen deprivation therapy produces significant early effects on waist circumference, body mass index, fasting glucose, triglycerides and cholesterol. The prevalence of and increase in the metabolic syndrome depend on the defining criteria. Counseling patients on the prevention, early detection and treatment of specific metabolic alterations is recommended.
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[Prostate cancer treated with androgen deprivation therapy: Care and monitoring in daily practice].
Hennequin, C, Bruyère, F, Sedefdjian, A, Bourouina, R, Rouprêt, M
Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie. 2015;(16):1132-9
Abstract
OBJECTIVE Our purpose was to identify measures implemented by urologists and radiation oncologists at the initiation of a 6-month formulation of luteinizing hormone releasing hormone (LHRH) agonist in patients with advanced PCa. MATERIAL This cross-sectional cohort survey was conducted during 6 months. Participants completed a questionnaire of 15 items on the first prescription of an androgen deprivation therapy (ADT), the parameters prescribed for monitoring and information provided to patients. RESULTS The median age of the 1100 enrolled patients was 75 years (range: 51-98 years); 245 patients (29.0%) were metastatic and 411 (39.4%) had a Gleason score ≥ 8. Prior to the treatment initiation, the dosage of the total testosterone was not very often performed (4.8%). Associated comorbidities such as arterial hypertension (53.6%) and hypercholesterolemia (31.8%) did not constitute a barrier to the initiation of ADT, alone (60.5%) or combined with anti-androgens (61%). According to the recommendations of the French Association of Urology (AFU), fasting glycemia was required in 427 patients (41.1%), lipid profile in 380 (36.1%), a blood count in 219 (21.1%) and bone densitometry in 111 (10.8%). The advice given to patients involved diet and lifestyle rules (61%). The potential risks of adverse events (AEs) mentioned were mainly hot flashes (95.5%). CONCLUSION Some recommendations seem insufficiently followed by the French specialists on information and monitoring procedures of ADT, especially in the cardiovascular field.