RESUMO
BACKGROUND: Testosterone treatment in men with hypogonadism improves bone density and quality, but trials with a sufficiently large sample and a sufficiently long duration to determine the effect of testosterone on the incidence of fractures are needed. METHODS: In a subtrial of a double-blind, randomized, placebo-controlled trial that assessed the cardiovascular safety of testosterone treatment in middle-aged and older men with hypogonadism, we examined the risk of clinical fracture in a time-to-event analysis. Eligible men were 45 to 80 years of age with preexisting, or high risk of, cardiovascular disease; one or more symptoms of hypogonadism; and two morning testosterone concentrations of less than 300 ng per deciliter (10.4 nmol per liter), in fasting plasma samples obtained at least 48 hours apart. Participants were randomly assigned to apply a testosterone or placebo gel daily. At every visit, participants were asked if they had had a fracture since the previous visit. If they had, medical records were obtained and adjudicated. RESULTS: The full-analysis population included 5204 participants (2601 in the testosterone group and 2603 in the placebo group). After a median follow-up of 3.19 years, a clinical fracture had occurred in 91 participants (3.50%) in the testosterone group and 64 participants (2.46%) in the placebo group (hazard ratio, 1.43; 95% confidence interval, 1.04 to 1.97). The fracture incidence also appeared to be higher in the testosterone group for all other fracture end points. CONCLUSIONS: Among middle-aged and older men with hypogonadism, testosterone treatment did not result in a lower incidence of clinical fracture than placebo. The fracture incidence was numerically higher among men who received testosterone than among those who received placebo. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).
Assuntos
Fraturas Ósseas , Hipogonadismo , Testosterona , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Densidade Óssea/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Método Duplo-Cego , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Hipogonadismo/sangue , Hipogonadismo/complicações , Hipogonadismo/tratamento farmacológico , Testosterona/administração & dosagem , Testosterona/efeitos adversos , Testosterona/sangue , Testosterona/farmacologia , Géis , Administração TópicaRESUMO
Background Preclinical studies have suggested that solid-state MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are useful measures of bone health. Purpose To explore whether MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are affected in postmenopausal osteoporosis (OP) and to examine associations between MRI markers and bone mineral density (BMD) in postmenopausal women. Materials and Methods In this single-center study, postmenopausal women were prospectively recruited from January 2019 to October 2020 into two groups: participants with OP who had not undergone treatment, defined as having any dual-energy x-ray absorptiometry (DXA) T-score of -2.5 or less, and age-matched control participants without OP (hereafter, non-OP). Participants underwent MRI in the midtibia, along with DXA in the hip and spine, and peripheral quantitative CT in the midtibia. Specifically, MRI measures of cortical bone porosity (pore water and total water), osteoid density (bound water [BW]), morphologic structure (cortical bone thickness), and mineralization (phosphorous [P] density [31P] and 31P-to-BW concentration ratio) were quantified at 3.0 T. MRI measures were compared between OP and non-OP groups and correlations with BMD were assessed. Results Fifteen participants with OP (mean age, 63 years ± 5 [SD]) and 19 participants without OP (mean age, 65 years ± 6) were evaluated. The OP group had elevated pore water (11.6 mol/L vs 9.5 mol/L; P = .007) and total water densities (21.2 mol/L vs 19.7 mol/L; P = .03), and had lower cortical bone thickness (4.8 mm vs 5.6 mm; P < .001) and 31P density (6.4 mol/L vs 7.5 mol/L; P = .01) than the non-OP group, respectively, although there was no evidence of a difference in BW or 31P-to-BW concentration ratio. Pore and total water densities were inversely associated with DXA and peripheral quantitative CT BMD (P < .001), whereas cortical bone thickness and 31P density were positively associated with DXA and peripheral quantitative CT BMD (P = .01). BW, 31P density, and 31P-to-BW concentration ratio were positively associated with DXA (P < .05), but not with peripheral quantitative CT. Conclusion Solid-state MRI of cortical bone was able to help detect potential impairments in parameters reflecting porosity, morphologic structure, and mineralization in postmenopausal osteoporosis. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae in this issue.
Assuntos
Osteoporose Pós-Menopausa , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Osteoporose Pós-Menopausa/diagnóstico por imagem , Porosidade , Densidade Óssea , Absorciometria de Fóton , Osso Cortical/diagnóstico por imagem , Água , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: To determine if testosterone treatment of men with unequivocal hypogonadism and organ-confined prostate cancer is associated with recurrence of the cancer. The testosterone dependence of metastatic prostate cancer has made physicians reluctant to treat hypogonadal men with testosterone even after treatment of prostate cancer. Prior studies of testosterone treatment of men with treated prostate cancer have not documented that the men were unequivocally hypogonadal. METHODS: A computerized search of electronic medical records from January 1, 2005, to September 20, 2021, identified 269 men aged ≥50 years who were diagnosed with prostate cancer and hypogonadism. We reviewed the individual records of these men and identified those treated by radical prostatectomy and had no evidence of extraprostatic extension. We then identified men who were hypogonadal prior to the diagnosis of prostate cancer based on at least 1 morning serum testosterone concentration of ≤220 ng/dL, discontinued testosterone treatment when the prostate cancer was diagnosed, resumed testosterone treatment within 2 years after treatment of the cancer, and were monitored for cancer recurrence, defined by a prostate-specific antigen level of ≥0.2 ng/mL. RESULTS: Sixteen men met the inclusion criteria. Their baseline serum testosterone concentrations were 9-185 ng/dL. The median duration of testosterone treatment and monitoring was 5 years (range, 1-20 years). None of the 16 men had biochemical recurrence of prostate cancer during this period. CONCLUSION: Testosterone treatment of men with unequivocal hypogonadism whose organ-confined prostate cancer is treated by radical prostatectomy may be safe.
Assuntos
Hipogonadismo , Neoplasias da Próstata , Masculino , Humanos , Testosterona/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Hipogonadismo/tratamento farmacológico , Antígeno Prostático Específico/uso terapêutico , Terapia de Reposição HormonalRESUMO
BACKGROUND: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial. METHODS: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. RESULTS: As of July 1, 2021, 5,076 subjects had been randomized. CONCLUSIONS: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.
Assuntos
Doenças Cardiovasculares , Sistema Cardiovascular , Hipogonadismo , Idoso , Doenças Cardiovasculares/etiologia , Método Duplo-Cego , Humanos , Hipogonadismo/induzido quimicamente , Hipogonadismo/complicações , Hipogonadismo/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Testosterona/uso terapêutico , Resultado do TratamentoRESUMO
As men age, their serum testosterone concentration falls, the total testosterone concentration barely but the free testosterone concentration more so. Testosterone treatment of older men who have low testosterone concentrations can ameliorate several consequences of this fall, including libido and sexual activity, distance walked, hemoglobin and volumetric bone mineral density and strength, but not vitality and cognitive function. The possibility that testosterone treatment of late-onset hypogonadism increases the risks of benign prostatic hyperplasia, prostate cancer or heart disease has been suggested but will not be determined until larger and longer trials are conducted.
Assuntos
Hipogonadismo , Testosterona , Masculino , Humanos , Idoso , Testosterona/uso terapêutico , Hipogonadismo/tratamento farmacológico , Densidade Óssea , Medição de RiscoRESUMO
INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.
Assuntos
Amiloidose , Disfunção Cognitiva , Humanos , Amiloide , Proteínas Amiloidogênicas , Apolipoproteína E4/genética , Biomarcadores , Encéfalo/metabolismo , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , Tomografia por Emissão de PósitronsRESUMO
There exists a public health imperative to discover and to develop disease-modifying Alzheimer's disease (AD) therapeutics to protect the health of millions of individuals facing AD. Achievement of this goal will be dependent on developing the clinical tools to detect high risk, in the earliest phases of the disease, and at the population level. This article describes the study of retinal biomarkers for the identification of, and tracking of change over time for, individuals in the preclinical stage of AD and substantiates the need for a major cross-disciplinary effort for comparison across labs and clinical sites using diabetes risk monitoring as a perfect analogy. Proposed framework would: (1) support AD working groups across disciplines; (2) establish common imaging platforms to develop and test basic standards, and minimum datasets to embrace and test novel innovations as they emerge; and (3) accelerate AD prevention and quality improvement in real-world care.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Diabetes Mellitus/terapia , Equipe de Assistência ao Paciente , Retina/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , População , Melhoria de Qualidade , Medição de RiscoRESUMO
In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico por imagem , Retina/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Encéfalo/diagnóstico por imagem , Humanos , Pessoa de Meia-IdadeRESUMO
The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Biomarcadores/análise , Disfunção Cognitiva/diagnóstico por imagem , Conhecimentos, Atitudes e Prática em Saúde , Programas de Rastreamento , Sintomas Prodrômicos , Doença de Alzheimer/patologia , Amiloide , Humanos , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. METHODS: We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. RESULTS: Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. CONCLUSIONS: In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).
Assuntos
Fadiga/tratamento farmacológico , Terapia de Reposição Hormonal , Comportamento Sexual/efeitos dos fármacos , Testosterona/uso terapêutico , Caminhada/fisiologia , Idoso , Depressão/tratamento farmacológico , Método Duplo-Cego , Humanos , Libido/efeitos dos fármacos , Masculino , Antígeno Prostático Específico/sangue , Valores de Referência , Comportamento Sexual/fisiologia , Testosterona/efeitos adversos , Testosterona/sangueRESUMO
Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a+/CD68+ M1 macrophages into the renal medulla. Renal inflammation is implicated in renal sodium retention and the development of hypertension. Renal denervation is known to decrease renal inflammation. The objective of this study was to determine the role of CD161a+/CD68+ macrophages and renal sympathetic nerves in cholinergic-hypertension and renal sodium retention. Bilateral renal nerve denervation (RND) and immune ablation of CD161a+ immune cells were performed in young prehypertensive spontaneously hypertensive rat (SHR) followed by infusion of either saline or nicotine (15 mg·kg-1·day-1) for 2 wk. Immune ablation was conducted by injection of unconjugated azide-free antibody targeting rat CD161a+. Blood pressure was monitored by tail cuff plethysmography. Tissues were harvested at the end of infusion. Nicotine induced premature hypertension, renal expression of the sodium-potassium chloride cotransporter (NKCC2), increases in renal sodium retention, and infiltration of CD161a+/CD68+ macrophages into the renal medulla. All of these effects were abrogated by RND and ablation of CD161a+ immune cells. Cholinergic activation of CD161a+ immune cells with nicotine leads to the premature development of hypertension in SHR. The effects of renal sympathetic nerves on chemotaxis of CD161a+ macrophages to the renal medulla, increased renal expression of NKCC2, and renal sodium retention contribute to cholinergic hypertension. The CD161a+ immune cells are necessary and essential for this prohypertensive nicotine-mediated inflammatory response.NEW & NOTEWORTHY This is the first study that describes a novel integrative physiological interaction between the adrenergic, cholinergic, and renal systems in the development of hypertension, describing data for the role of each in a genetic model of essential hypertension. Noteworthy findings include the prevention of nicotine-mediated hypertension following successful immune ablation of CD161a+ immune cells and the necessary role these cells play in the overexpression of the sodium-potassium-chloride cotransporter (NKCC2) in the renal medulla and renal sodium retention. Renal infiltration of these cells is demonstrated to be dependent on the presence of renal adrenergic innervation. These data offer a fertile ground of therapeutic potential for the treatment of hypertension as well as open the door for further investigation into the mechanism involved in inflammation-mediated renal sodium transporter expression. Taken together, these findings suggest immune therapy, renal denervation, and, possibly, other new molecular targets as having a potential role in the development and maintenance of essential hypertension.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Pressão Sanguínea , Hipertensão/prevenção & controle , Rim , Macrófagos/efeitos dos fármacos , Subfamília B de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Nicotina , Agonistas Nicotínicos , Fenol/administração & dosagem , Artéria Renal/inervação , Reabsorção Renal , Sódio/urina , Simpatectomia Química , Animais , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/imunologia , Hipertensão/fisiopatologia , Mediadores da Inflamação/imunologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/imunologia , Macrófagos/imunologia , Masculino , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Ratos Endogâmicos SHR , Membro 1 da Família 12 de Carreador de Soluto/metabolismoRESUMO
BACKGROUND: A recent study of older men participating in the Testosterone Trials (TTrials) defined a clinically meaningful change in the Psychosexual Daily Questionnaire (PDQ) question 4 in hypogonadal men age ≥65 years. This study defines clinically meaningful change in the same population for sexual desire assessed by PDQ question 1. AIM: To determine a clinically meaningful change in the answers to question 1 of the PDQ in hypogonadal older men. METHODS: Participants in the Sexual Function Trial of the TTrials were randomly divided into a training and test set. Anchor-based methods, including regression analysis, receiver operating characteristic curves, and empirical cumulative distribution functions, were used to determine a clinically meaningful change on question 1 in the training set, and the selected threshold was evaluated in the test set for an effect of testosterone treatment. RESULTS: A clinically meaningful increase in question 1 of the PDQ was determined to be ≥0.7 points. CLINICAL IMPLICATIONS: Question 1 of the PDQ can be used to assess sexual desire in response to testosterone treatment. STRENGTHS & LIMITATIONS: Data were obtained from a single large study of older hypogonadal men. CONCLUSION: Clinically meaningful improvement of sexual desire is a change of ≥0.7 in the score of question 1 of the PDQ. Stephens-Shields AJ, Wang C, Preston P, et al. Clinically Meaningful Change in Sexual Desire in the Psychosexual Daily Questionnaire in Older Men from the TTrials. J Sex Med 2019;16:951-953.
Assuntos
Libido/efeitos dos fármacos , Comportamento Sexual/efeitos dos fármacos , Testosterona/uso terapêutico , Idoso , Humanos , Masculino , Inquéritos e QuestionáriosRESUMO
Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-ß proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Neurônios Colinérgicos/fisiologia , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Colinérgicos/metabolismo , Colinérgicos/uso terapêutico , Neurônios Colinérgicos/metabolismo , Inibidores da Colinesterase/metabolismo , Cognição/fisiologia , Transtornos Cognitivos/etiologia , Humanos , Emaranhados Neurofibrilares/metabolismoRESUMO
BACKGROUND: Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function. AIM: To determine reliability of PDQ and DISF-II by assessing the correlation within and between domains in the questionnaires and to define clinically meaningful changes in sexual activity (PDQ question 4 [Q4]) and desire (DISF-II sexual desire domain [SDD]) domains. METHODS: Data from 470 men participating in the T Trials were used to calculate Spearman correlation coefficients of individual items and total score among questionnaires to determine convergent and construct validity. Clinically meaningful changes for sexual desire and activity were determined by randomly dividing the sample into training and validation sets. Anchor- and distribution-based clinically meaningful change criteria were defined in the training set, and selected changes were evaluated in the validation set. OUTCOMES: Validity of the PDQ and DISF-II and clinically meaningful changes in sexual desire and activity were determined in older men in T Trials. RESULTS: Moderate to strong correlations were shown within and between domains from different questionnaires. Using Patient Global Impression of Change as an anchor, clinically meaningful change in PDQ sexual activity was ≥0.6, and in DISF-SDD was ≥5.0. Applying these change cut-points to the validation set, a greater proportion of T-treated men achieved clinically meaningful improvement in their sexual desire and activity compared to placebo-treated men. CLINICAL IMPLICATIONS: The PDQ-Q4 and DISF-II-SDD can be used to reliably assess clinically meaningful changes in sexual activity and sexual desire in hypogonadal men treated with T. STRENGTHS & LIMITATIONS: Strengths of this study include a large sample size, long trial duration, and inclusion of men with low libido and unequivocally low T levels. Limitations include using data from a single study that enrolled only older hypogonadal men, and only 1 anchor for both sexual desire and activity. CONCLUSION: Moderate to strong correlations were demonstrated within and between different sexual domains of the PDQ and DISF-II confirming construct and convergent validity. Clinically meaningful improvement in elderly hypogonadal men was change of ≥0.6 score in the PDQ-Q4 and ≥5.0 in the DISF-SDD. Improvements in sexual activity and desire in the T Trials were modest but clinically meaningful. Wang C, Stephens-Shields AJ, DeRogatis LR, et al. Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 2018;15:997-1009.
Assuntos
Libido/efeitos dos fármacos , Comportamento Sexual/psicologia , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Disfunções Sexuais Fisiológicas/psicologia , Inquéritos e Questionários/normas , Testosterona/sangue , Idoso , Método Duplo-Cego , Humanos , Masculino , Ereção Peniana/efeitos dos fármacos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. METHODS: In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. RESULTS: Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. CONCLUSIONS: As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).
Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Nitrilas/uso terapêutico , Síndrome do Ovário Policístico/complicações , Triazóis/uso terapêutico , Adulto , Clomifeno/efeitos adversos , Clomifeno/farmacologia , Método Duplo-Cego , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Fármacos para a Fertilidade Feminina/farmacologia , Humanos , Infertilidade Feminina/etiologia , Estimativa de Kaplan-Meier , Letrozol , Nascido Vivo , Fase Luteal , Masculino , Nitrilas/efeitos adversos , Nitrilas/farmacologia , Ovulação/efeitos dos fármacos , Gravidez , Qualidade de Vida , Triazóis/efeitos adversos , Triazóis/farmacologiaRESUMO
SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-ß-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-ß in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-ß and cerebrospinal fluid amyloid-ß42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-ß levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-ß on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-ß in autosomal dominant Alzheimer's disease.
Assuntos
Doença de Alzheimer/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Hipocampo/fisiologia , Transtornos da Memória/genética , Metionina/genética , Valina/genética , Proteínas tau/genética , Adulto , Doença de Alzheimer/diagnóstico por imagem , Feminino , Heterozigoto , Hipocampo/diagnóstico por imagem , Humanos , Masculino , Transtornos da Memória/diagnóstico por imagem , Pessoa de Meia-IdadeRESUMO
Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk. Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume. Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014. Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis). Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group. Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.
Assuntos
Androgênios/efeitos adversos , Doença da Artéria Coronariana/induzido quimicamente , Doença da Artéria Coronariana/diagnóstico por imagem , Terapia de Reposição Hormonal/efeitos adversos , Testosterona/efeitos adversos , Calcificação Vascular/diagnóstico por imagem , Idoso , Androgênios/administração & dosagem , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Progressão da Doença , Método Duplo-Cego , Géis , Humanos , Hipogonadismo/sangue , Hipogonadismo/tratamento farmacológico , Masculino , Variações Dependentes do Observador , Tamanho da Amostra , Testosterona/administração & dosagem , Testosterona/sangue , Estados UnidosRESUMO
Importance: Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions. Objective: To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). Design, Setting, and Participants: The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014. Interventions: Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. Main Outcomes and Measures: The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. Results: Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89). Conclusions and Relevance: Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.
Assuntos
Androgênios/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Testosterona/uso terapêutico , Idoso , Cognição/efeitos dos fármacos , Cognição/fisiologia , Método Duplo-Cego , Função Executiva/efeitos dos fármacos , Função Executiva/fisiologia , Géis , Humanos , Análise de Intenção de Tratamento , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Transtornos da Memória/sangue , Transtornos da Memória/etiologia , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Valores de Referência , Testosterona/sangue , Fatores de Tempo , Resultado do TratamentoRESUMO
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