RESUMO
BACKGROUND: Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain. METHODS: One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS: As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS: Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00114114. FUNDING: AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.
Assuntos
Eunuquismo/tratamento farmacológico , Osteoporose/prevenção & controle , Testosterona/administração & dosagem , Adulto , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea , Estradiol/sangue , Eunuquismo/sangue , Eunuquismo/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/sangue , Osteoporose/etiologia , Testosterona/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
Consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a survival benefit to patients with acute lymphoblastic leukemia (ALL). We have previously reported comparable survival and relapse rates after T cell-depleted (TCD) allo-HSCT compared with unmodified transplantations for acute myelogenous leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma with significantly decreased graft-versus-host disease (GVHD). We performed a 56-patient retrospective study to evaluate TCD allo-HSCT for the treatment of ALL after myeloablative total body irradiation-based therapy. The 2-year and 5-year overall survival rates for patients with ALL after TCD allo-HSCT were 0.39 (95% confidence interval [CI], 0.26-0.52) and 0.32 (95% CI, 0.19-0.44), respectively, and the 2-year and 5-year disease-free survival rates were 0.38 (95% CI, 0.25-0.50) and 0.32 (95% CI, 0.20-0.44). There was a trend toward improved survival of patients who underwent TCD allo-HSCT in first complete remission compared with those who did so in other remission states. The cumulative incidence of grade II-IV acute GVHD at 1 year was 0.20 (95% CI, 0.10-0.31), and no patients developed grade IV acute GVHD. The cumulative incidence of chronic GVHD in 41 evaluable patients at 2 and 5 years was 0.15 (95% CI, 0.04-0.26), and that of extensive chronic GVHD at 2 and 5 years was 0.05 (95% CI, 0-11.6). We demonstrate OS and DFS rates that compare favorably to unmodified allo-HSCT with lower rates of GVHD.
Assuntos
Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Adolescente , Adulto , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: The m.3243A>G mutation can cause multisystem medical problems and can affect the autonomic nervous system. OBJECTIVE: To study the frequency and spectrum of autonomic symptoms associated with the m.3243A>G mitochondrial DNA point mutation. Design, Setting, and Patients We studied a cohort of 88 matrilineal relatives from 40 families, including 35 fully symptomatic patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), 53 carrier relatives, and 16 controls using a questionnaire based on existing standard instruments for the evaluation of autonomic dysfunction. We compared the questionnaire with an expert evaluation. We compared data among the 3 groups using the Mantel-Haenszel chi(2) test to determine the statistical significance of differences between groups. RESULTS: Mutation carriers frequently had symptoms of autonomic dysfunction, specifically gastrointestinal and orthostatic intolerance. CONCLUSIONS: Carriers of the m.3243A>G mutation have frequent autonomic symptoms. The m.3243A>G mutation should be considered as an etiological factor in patients with autonomic dysfunction and a medical or family history suggestive of mitochondrial disease. Because some autonomic symptoms are treatable, early detection and proactive management may mitigate the burden of morbidity.