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Rhonda R Voskuhl - One of the best experts on this subject based on the ideXlab platform.
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Estriol mediated neuroprotection in multiple sclerosis localized by voxel based morphometry
Brain and behavior, 2018Co-Authors: Allan Mackenziegraham, Hejing Wang, Florian Kurth, Jenny Brook, Yuichiro Itoh, Cassandra Meyer, Michael Montag, Robert Elashoff, Rhonda R VoskuhlAbstract:Author(s): MacKenzie-Graham, Allan; Brook, Jenny; Kurth, Florian; Itoh, Yuichiro; Meyer, Cassandra; Montag, Michael J; Wang, He-Jing; Elashoff, Robert; Voskuhl, Rhonda R | Abstract: IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of Estriol treatment in women with relapsing-remitting MS (RRMS), higher Estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in Estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty-two Estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans.ResultsA region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in Estriol- as compared to placebo-treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability-specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in Estriol-treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during Estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.
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bedside to bench to bedside research estrogen receptor beta ligand as a candidate neuroprotective treatment for multiple sclerosis
Journal of Neuroimmunology, 2017Co-Authors: Noriko Itoh, Roy Y Kim, Mavis S Peng, Emma Difilippo, Hadley Johnsonbaugh, Allan Mackenziegraham, Rhonda R VoskuhlAbstract:Protective effects of pregnancy during MS have led to clinical trials of Estriol, the pregnancy estrogen, in MS. Since Estriol binds to estrogen receptor (ER) beta, ER beta ligand could represent a "next generation Estriol" treatment. Here, ER beta ligand treatment was protective in EAE in both sexes and across genetic backgrounds. Neuroprotection was shown in spinal cord, sparing myelin and axons, and in brain, sparing neurons and synapses. Longitudinal in vivo MRIs showed decreased brain atrophy in cerebral cortex gray matter and cerebellum during EAE. Investigation of ER beta ligand as a neuroprotective treatment for MS is warranted.
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Estriol combined with glatiramer acetate for women with relapsing remitting multiple sclerosis a randomised placebo controlled phase 2 trial
Lancet Neurology, 2016Co-Authors: Rhonda R Voskuhl, Noriko Itoh, Nancy L Sicotte, Hejing Wang, T Jackson C Wu, Kunio Nakamura, Florian Kurth, Jenny Bardens, Jacqueline Bernard, John R CorboyAbstract:Summary Background Relapses of multiple sclerosis decrease during pregnancy, when the hormone Estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis Estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether Estriol treatment reduces multiple sclerosis relapses in women. Methods We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18–50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral Estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0·10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. Findings We enrolled 164 patients: 83 were allocated to the Estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0·25 relapses per year (95% CI 0·17–0·37) in the Estriol group versus 0·37 relapses per year (0·25–0·53) in the placebo group (adjusted rate ratio 0·63, 95% CI 0·37–1·05; p=0·077). The proportion of patients with serious adverse events did not differ substantially between the Estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the Estriol group than in the placebo group (19 [23%] vs three [4%], p=0·0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0·0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. Interpretation Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. Funding National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.
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Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis implications for multiple sclerosis
Journal of Neuroimmunology, 2004Co-Authors: Karen Palaszynski, Hongbiao Liu, Kyi Kyi Loo, Rhonda R VoskuhlAbstract:Estrogen treatment has been found to be protective in experimental autoimmune encephalomyelitis (EAE) and possibly multiple sclerosis (MS). We investigated whether the effect of estrogen treatment is gender-specific. Estrogen receptor (ER) expressions, ERalpha and ERbeta, were found to be equivalent in both genders. EAE disease severity in both females and males was decreased with Estriol treatment as compared to placebo. Finally, proinflammatory cytokine production during autoantigen-specific immune responses was decreased with Estriol treatment in both females and males. These data support a potential role for Estriol treatment for men in addition to women with MS.
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immune modulation in multiple sclerosis patients treated with the pregnancy hormone Estriol
Journal of Immunology, 2003Co-Authors: Samantha S Soldan, Nancy L Sicotte, Ana Alvarez I Retuerto, Rhonda R VoskuhlAbstract:The protective effect of pregnancy on putative Th1-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, is associated with a Th1 to Th2 immune shift during pregnancy. The hormone Estriol increases during pregnancy and has been shown to ameliorate experimental autoimmune encephalomyelitis and collagen-induced arthritis. In addition, estrogens induce cytokine changes consistent with a Th1 to Th2 shift when administered in vitro to human immune cells and in vivo to mice. In a pilot trial, oral Estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging. Here, the immunomodulatory effects of oral Estriol therapy were assessed. PBMCs collected longitudinally during the trial were stimulated with mitogens, recall Ags, and glatiramer acetate. Cytokine profiles of stimulated PBMCs were determined by intracellular cytokine staining (IL-5, IL-10, IL-12 p40, TNF-α, and IFN-γ) and cytometric bead array (IL-2, IL-4, IL-5, IL-10, TNF-α, and IFN-γ). Significantly increased levels of IL-5 and IL-10 and decreased TNF-α were observed in stimulated PBMC isolated during Estriol treatment. These changes in cytokines correlated with reductions of enhancing lesions on magnetic resonance imaging in relapsing remitting multiple sclerosis. The increase in IL-5 was primarily due to an increase in CD4+ and CD8+ T cells, the increase in IL-10 was primarily due to an increase in CD64+ monocytes/macrophages with some effect in T cells, while the decrease in TNF-α was primarily due to a decrease in CD8+ T cells. Further study of oral Estriol therapy is warranted in Th1-mediated autoimmune diseases with known improvement during pregnancy.
Walter E Stamm - One of the best experts on this subject based on the ideXlab platform.
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effectiveness of Estriol containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women
Clinical Infectious Diseases, 2003Co-Authors: R Raz, Raul Colodner, Y Rohana, S Battino, E Rottensterich, I Wasser, Walter E StammAbstract:We compared the efficacy and safety of Estriol-containing vaginal pessary use with those of oral nitrofurantoin macrocrystal (NM) therapy for preventing urinary tract infection (UTI) in postmenopausal women with recurrent UTI. Over a period of 9 months, 86 women received an Estriol-containing vaginal pessary (0.5 mg Estriol) twice weekly, and 85 women received NM (100 mg) once daily. We recorded 124 episodes of UTI in women who received Estriol-releasing pessaries and 48 episodes of UTI in women treated with NM (P=.0003). Twenty-eight women (32.6%) who received Estriol had no episodes of UTI versus 41 women (48.2%) in the NM group. There was a significant increase in the number of superficial cells in women who received Estriol, whereas in the NM group, no such changes occurred. However, there was no change in the extent of Lactobacillus colonization and in the vaginal pH in women who received Estriol. Use of an Estriol-containing pessary is less effective than oral NM therapy in the prevention of bacteriuria in postmenopausal women because of its failure to restore the population of lactobacilli and to reduce the vaginal pH in these women.
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a controlled trial of intravaginal Estriol in postmenopausal women with recurrent urinary tract infections
The New England Journal of Medicine, 1993Co-Authors: R Raz, Walter E StammAbstract:Background Recurrent urinary tract infections are a problem for many postmenopausal women. Estrogen replacement restores atrophic mucosa, lowers vaginal pH, and may prevent urinary tract infections. Methods We enrolled 93 postmenopausal women with a history of recurrent urinary tract infections in a randomized, double-blind, placebo-controlled trial of a topically applied intravaginal Estriol cream. Midstream urine cultures were obtained at enrollment, monthly for eight months, and whenever urinary symptoms occurred. Vaginal cultures and pH measurements were obtained at entry and after one and eight months. The women were assigned to receive either Estriol (n = 50) or placebo (n = 43), both administered intravaginally; 36 and 24, respectively, completed the eight months of follow-up. Results The incidence of urinary tract infection in the group given Estriol was significantly reduced as compared with that in the group given placebo (0.5 vs. 5.9 episodes per patient-year, P<0.001). Survival analysis showed...
R Raz - One of the best experts on this subject based on the ideXlab platform.
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effectiveness of Estriol containing vaginal pessaries and nitrofurantoin macrocrystal therapy in the prevention of recurrent urinary tract infection in postmenopausal women
Clinical Infectious Diseases, 2003Co-Authors: R Raz, Raul Colodner, Y Rohana, S Battino, E Rottensterich, I Wasser, Walter E StammAbstract:We compared the efficacy and safety of Estriol-containing vaginal pessary use with those of oral nitrofurantoin macrocrystal (NM) therapy for preventing urinary tract infection (UTI) in postmenopausal women with recurrent UTI. Over a period of 9 months, 86 women received an Estriol-containing vaginal pessary (0.5 mg Estriol) twice weekly, and 85 women received NM (100 mg) once daily. We recorded 124 episodes of UTI in women who received Estriol-releasing pessaries and 48 episodes of UTI in women treated with NM (P=.0003). Twenty-eight women (32.6%) who received Estriol had no episodes of UTI versus 41 women (48.2%) in the NM group. There was a significant increase in the number of superficial cells in women who received Estriol, whereas in the NM group, no such changes occurred. However, there was no change in the extent of Lactobacillus colonization and in the vaginal pH in women who received Estriol. Use of an Estriol-containing pessary is less effective than oral NM therapy in the prevention of bacteriuria in postmenopausal women because of its failure to restore the population of lactobacilli and to reduce the vaginal pH in these women.
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a controlled trial of intravaginal Estriol in postmenopausal women with recurrent urinary tract infections
The New England Journal of Medicine, 1993Co-Authors: R Raz, Walter E StammAbstract:Background Recurrent urinary tract infections are a problem for many postmenopausal women. Estrogen replacement restores atrophic mucosa, lowers vaginal pH, and may prevent urinary tract infections. Methods We enrolled 93 postmenopausal women with a history of recurrent urinary tract infections in a randomized, double-blind, placebo-controlled trial of a topically applied intravaginal Estriol cream. Midstream urine cultures were obtained at enrollment, monthly for eight months, and whenever urinary symptoms occurred. Vaginal cultures and pH measurements were obtained at entry and after one and eight months. The women were assigned to receive either Estriol (n = 50) or placebo (n = 43), both administered intravaginally; 36 and 24, respectively, completed the eight months of follow-up. Results The incidence of urinary tract infection in the group given Estriol was significantly reduced as compared with that in the group given placebo (0.5 vs. 5.9 episodes per patient-year, P<0.001). Survival analysis showed...
Jeffrey B Gould - One of the best experts on this subject based on the ideXlab platform.
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risk of bronchopulmonary dysplasia by second trimester maternal serum levels of α fetoprotein human chorionic gonadotropin and unconjugated Estriol
Pediatric Research, 2012Co-Authors: Laura L Jelliffepawlowski, Gary M Shaw, David K Stevenson, John Oehlert, Cele Quaintance, Allan J Santos, Rebecca J Baer, Robert Currier, Hugh Obrodovich, Jeffrey B GouldAbstract:Risk of bronchopulmonary dysplasia by second-trimester maternal serum levels of α-fetoprotein, human chorionic gonadotropin, and unconjugated Estriol
Concepcion Nietomagro - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of ultra low dose 0 005 Estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors a phase ii randomized double blind placebo controlled trial
Menopause, 2020Co-Authors: Angelica Linden Hirschberg, Pedro Sanchezrovira, Jesus Presalorite, Miriam Camposdelgado, Miguel Gilgil, Elisabet Lidbrink, Javier Suarezalmarza, Concepcion NietomagroAbstract:Objective To assess the efficacy and safety of ultra-low dose 0.005% Estriol vaginal gel in women with breast cancer receiving nonsteroidal aromatase inhibitors (NSAIs) and experiencing treatment-related vulvovaginal symptoms and signs. Methods Women with hormone receptor-positive early breast cancer receiving NSAIs were randomized to either Estriol vaginal gel or placebo for 12 weeks. Vaginal maturation, vaginal pH, and total and individual scores of symptoms and signs of vulvovaginal atrophy were assessed at baseline and at weeks 3 and 12; sexual functioning was also evaluated using the Female Sexual Functioning Index (FSFI) questionnaire, as well as circulating estrogens, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Results Sixty-one women with a mean age of 59 years were included: 50 received 0.005% Estriol vaginal gel and 11 received placebo. Active treatment significantly improved maturation value and pH, vaginal dryness and global scores of symptoms and signs. Active treatment also increased the total FSFI score and all the FSFI domains, with the exception of pain. Small oscillations were observed in FSH and LH, which remained within the postmenopausal range. Estriol levels increased initially and normalized by week 12, and estradiol and estrone remained mostly undetectable throughout the study. Conclusions Ultra-low dose 0.005% Estriol vaginal gel showed efficacy in improving the symptoms and signs of vulvovaginal atrophy. These results, together with minimal oscillations in hormonal levels throughout the treatment, support the use of ultra-low dose 0.005% Estriol vaginal gel as a treatment option for vulvovaginal atrophy in women with breast cancer receiving NSAIs with an indication for treatment with vaginal estrogens. : Video Summary:http://links.lww.com/MENO/A531.