Effect of leuprorelin in bulbar function of spinal and bulbar muscular atrophy patients: observational study for 1 year

Kang, Min‐Gu; Gwak, Dae-Won; Cho, Hee Jin; Min, Yu-Sun; Park, Jin-Sung

doi:10.1007/s00415-021-10503-y

Cited by 7 publications

(6 citation statements)

References 34 publications

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“…The pathophysiology of SBMA is based on mutant androgen receptors, making hormone profiles and hormone-targeted therapies highly relevant to patients with SBMA. [34][35][36] FSH and LH levels tend to be elevated from their normal values. 30 Furthermore, LH levels demonstrate negative correlation with clinical scales, 4 whereas testosterone levels demonstrate positive correlation with the clinical scales.…”

Section: Discussionmentioning

confidence: 94%

Whole‐Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study

Kim,

Seo,

Kang

et al. 2023

Annals of Neurology

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ObjectiveSpinal and bulbar muscular atrophy (SBMA) is characterized by slow, progressive bulbar and limb muscle weakness; however, the pattern of progression of muscle fat infiltration remains unclear. We assessed the progression of muscle involvement in 81 patients with SBMA using whole‐body muscle magnetic resonance imaging (MRI), alongside clinical and laboratory findings.MethodsThis prospective study included patients with genetically confirmed SBMA who underwent whole‐body muscle MRI. We analyzed muscle fat infiltration and the pattern of involved muscles using cluster analysis, visualizing the sequential progression of fat infiltration. Muscle clusters demonstrated correlation with clinical scales and laboratory findings. Additionally, linear regression analysis was performed to identify the MRI section most strongly associated with 6‐minute walk test (6MWT).ResultsWe included 81 patients with SBMA (age = 54.3 years). After categorizing the patients into 6 clusters based on the pattern of muscle fat infiltration, we observed that muscle involvement began in the posterior calf and progressed to the posterior thigh, pelvis, trunk, anterior thigh, medial thigh, anterior calf, and upper extremity muscles. These muscle clusters correlated significantly with disease duration (τ = 0.47, p < 0.001), 6MWT (τ = −0.49, p < 0.001), and serum creatinine level (τ = −0.46, p < 0.001). The whole‐body MRI indicated the thigh as the section most significantly correlated with 6MWT.InterpretationWe used whole‐body muscle MRI to determine the sequential progression of the fat infiltration in SBMA. Our findings may enable the identification of objective and reliable imaging outcome measures in the study of the natural history or future clinical trials of SBMA. ANN NEUROL 2023

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Section: Discussionmentioning

confidence: 94%

Whole‐Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study

Kim,

Seo,

Kang

et al. 2023

Annals of Neurology

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“…Dutasteride, a 5alpha-reductase inhibitor that blocks testosterone conversion into its more active metabolite dihydrotestosterone, failed to reduce disease progression in a phase 2 trial, but reduced the number of falls in treated patients [26], a measure that resembles rotarod data found in our study in mice. On the contrary, leuprorelin, a GnRH agonist, diminished nuclear ARpolyQ aggregates and rescued motor dysfunctions in a SBMA mouse model [21], and ameliorated the swallowing function in SBMA patients without any severe adverse effect [20,23,[56][57][58]. The nonsteroidal AR antagonist flutamide had no effect on the phenotypic expression of SBMA [21], but protected different mouse SBMA models from AR toxicity if combined with treatments lowering androgen production [21,25]; notably, flutamide suppressed AR transactivation, but it did not inhibit ARpolyQ nuclear translocation that is the main pathogenic mechanism of SBMA.…”

Section: Discussionmentioning

confidence: 96%

“…To date, several therapeutic strategies aimed either at diminishing androgen levels or at competing with androgens to block ARpolyQ activation and toxicity have been tested in mouse models of SBMA. Surgical castration ameliorates symptomatology in transgenic (Tg) SBMA mouse models [12], and chemical castration with leuprorelin [a gonadotropinreleasing hormone (GnRH) agonist that reduces testosterone release from the testis] rescues motor dysfunction and reduces ARpolyQ aggregation in SBMA mice [20,21]. Unfortunately, leuprorelin in patients was less efficient than in mice [22], even if some benefits were proved [23].…”

Section: Introductionmentioning

confidence: 99%

Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice

et al. 2023

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Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.

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“…In this work, the authors found that the production of nitric oxide, costimulated with lipopolysaccharide (LPS) and interferon- γ (IFNy), and the activity of NF- κ B were suppressed by GnRH exposure. These results demonstrate that GnRH participates in macrophage function and indicate that the NF- κ B signaling pathway may be responsible for GnRH-mediated immune modulation [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…There are two works evaluating the efficacy of the GnRH-analogue, leuprolide acetate, on NK cell activity. The first one suggests an increased NK cell activity in peripheral blood samples determined by 51Cr release assay 3 Case Reports in Urology [8], and the second one reported that NK cell cytotoxicity from control and patients was significantly decreased with leuprolide acetate [9]. These findings suggest a direct immunomodulatory role of GnRH on NK cell activity.…”

Section: Discussionmentioning

confidence: 99%

Diffuse Leukoplakia of the Bladder Ostium-Sparing in Patient Treated with Leuprorelin for Breast Cancer

Nacchia

Giacomo

Cerbo

et al. 2021

Case Reports in Urology

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Case. A 55-year-old woman came to our attention in April 2020 referring haematuria, frequency and urgency. The patient referred previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer three years ago. Urine culture was performed and resulted always negative for pathogens. Cystoscopy revealed a whitish plaque lesion on the fundus, dome, trigone, and left lateral wall of the bladder. Histology of the biopsy confirmed the diagnosis of leukoplakia of the bladder. The plan is to follow her up repeating a cystoscopy every three months and biopsy in 6 months. Literature search revealed very little information on pathogenesis and prognosis of this condition due to its rare occurrence. The main objective of our case study was to describe individual situation of a woman affected by diffuse leukoplakia of the bladder ostium-sparing with a previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer and to show safety of follow-up by cystoscopy and biopsy. Conclusions. We showed a case of a woman treated with leuprorelin and with diffuse leukoplakia of the bladder. We support the recommended long-term follow-up and surveillance based on the literature review by cystoscopy with or without biopsy.

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Effect of leuprorelin in bulbar function of spinal and bulbar muscular atrophy patients: observational study for 1 year

Cited by 7 publications

References 34 publications

Whole‐Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study

Whole‐Body Muscle Magnetic Resonance Imaging in 81 Patients with Spinal and Bulbar Muscular Atrophy: A Prospective Study

Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice

Diffuse Leukoplakia of the Bladder Ostium-Sparing in Patient Treated with Leuprorelin for Breast Cancer

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