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1.
Safety and clinical outcome of tamoxifen in Duchenne muscular dystrophy.
Tsabari, R, Simchovitz, E, Lavi, E, Eliav, O, Avrahami, R, Ben-Sasson, S, Dor, T
Neuromuscular disorders : NMD. 2021;(9):803-813
Abstract
Patients having Duchenne muscular dystrophy (DMD) are currently being treated with corticosteroids, which slow down disease progression at the expense of serious adverse effects. Tamoxifen is a pro-drug some of whose metabolites interact with the nuclear estrogen receptor, leading to anti-fibrotic and muscle-protective effects as has been demonstrated in a murine model of DMD. Here we report the results from a monocentric single arm prospective study in 13 ambulant boys aged 6-14 years with genetically confirmed DMD, aimed to assess the safety of tamoxifen and its impact on disease progression. Boys were treated for up to 3 years with 20 mg/day of oral tamoxifen, in addition to their ongoing corticosteroid treatment. For 8 of these patients, outcome was compared to an age- and performance-matched 12-month natural history dataset. The primary end point was the 6-minute walk test. Secondary end points were the NorthStar assessment, timed function tests, pulmonary function, the biomarker creatine phosphokinase and adverse effects. No adverse effects were noticed other than mild gynecomastia in 4 boys. Tamoxifen-treated patients retained motor and respiratory function, compared with a significant deterioration of age-matched historical control patients receiving corticosteroids only. These encouraging findings warrant a larger clinical trial to substantiate the use of tamoxifen in Duchenne muscular dystrophy.
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2.
Retinal structural changes in patients receiving tamoxifen therapy by spectral-domain optical coherence tomography.
Bolukbasi, S, Kandemir Gursel, O, Cakir, A, Erden, B, Karatas, G
Cutaneous and ocular toxicology. 2020;(2):115-121
Abstract
Purpose: To evaluate choroidal thickness, ganglion cell complex (GCC) and photoreceptor outer segment (PROS) length were measured in patients with breast cancer undergoing tamoxifen therapy, using spectral-domain optical coherence tomography (SD-OCT); results were compared with those for normal eyes.Materials and methods: Forty-four patients with breast cancer, undergoing tamoxifen therapy, and 41 healthy controls were included in this prospective, comparative study. All participants underwent a complete ophthalmologic evaluation and SD-OCT. Subfoveal, nasal (nasal distance to fovea 500, 1000, 1500 μm), and temporal (temporal distance to fovea 500, 1000, 1500 μm) choroidal thickness measurements were performed using the enhanced depth imaging mode of SD-OCT. Using an Early Treatment Diagnostic Retinopathy Study (ETDRS) circle at the macular level, the automated retinal segmentation software was applied to determine the thickness of the GCC. PROS length was determined manually, as the distance from the inner surface of the ellipsoid zone to the inner surface of retina pigment epithelium.Results: The mean choroidal thickness was statistically greater in the tamoxifen group than controls in all quadrants (p < 0.001 for all quadrants). Of all tamoxifen users (44 eyes of 44 patients), 33 eyes (75%) had uncomplicated pachychoroid (UCP). Pachychoroid pigment epitheliopathy (PPE) was detected in five tamoxifen-group patients (11.3%). Patients with PPE in one eye had UCP in the fellow eye. Central serous chorioretinopathy findings were observed in one patient. Tamoxifen users had statistically lower GCC thickness in all inner rings of the ETDRS inlay and in the nasal outer ring only (p = 0.027, 0.002, 0.002, 0.001, and 0.030, respectively). No statistically significant difference in mean subfoveal PROS length was found between the groups.Conclusions: SD-OCT provides valuable information for identifying structural changes and evaluating ocular findings in patients receiving tamoxifen therapy. Increased choroidal thickness, PPE and thinning GCC were detected in tamoxifen users. These OCT findings may be an early indicator of retinal toxicity for patients undergoing tamoxifen therapy in the follow-up period.
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3.
Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis.
Barrionuevo, P, Kapoor, E, Asi, N, Alahdab, F, Mohammed, K, Benkhadra, K, Almasri, J, Farah, W, Sarigianni, M, Muthusamy, K, et al
The Journal of clinical endocrinology and metabolism. 2019;(5):1623-1630
Abstract
BACKGROUND Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. METHODS We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. RESULTS We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with progesterone, and vitamin D. A significant reduction in vertebral fractures was observed with abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, strontium ranelate, denosumab, zoledronate, risedronate, alendronate, ibandronate, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin. Teriparatide, abaloparatide, denosumab, and romosozumab were associated with the highest relative risk reductions, whereas ibandronate and selective estrogen receptor modulators had lower efficacy. The evidence for the treatment of fractures with vitamin D and calcium remains limited despite numerous large trials. CONCLUSIONS This network meta-analysis provides comparative effective estimates for the various available treatments to reduce the risk of fragility fractures in postmenopausal women.
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4.
Alternatives to Testosterone Therapy: A Review.
Lo, EM, Rodriguez, KM, Pastuszak, AW, Khera, M
Sexual medicine reviews. 2018;(1):106-113
Abstract
INTRODUCTION Although testosterone therapy (TTh) is an effective treatment for hypogonadism, recent concerns regarding its safety have been raised. In 2015, the US Food and Drug Administration issued a warning about potential cardiovascular risks resulting from TTh. Fertility preservation is another reason to search for viable alternative therapies to conventional TTh, and in this review we evaluate the literature examining these alternatives. AIMS To review the role and limitations of non-testosterone treatments for hypogonadism. METHODS A literature search was conducted using PubMed to identify relevant studies examining medical and non-medical alternatives to TTh. Search terms included hypogonadism, testosterone replacement therapy, testosterone therapy, testosterone replacement alternatives, diet and exercise and testosterone, varicocele repair and testosterone, stress reduction and testosterone, and sleep apnea and testosterone. MAIN OUTCOME MEASURES Review of peer-reviewed literature. RESULTS Medical therapies examined include human chorionic gonadotropins, aromatase inhibitors, and selective estrogen receptor modulators. Non-drug therapies that are reviewed include lifestyle modifications including diet and exercise, improvements in sleep, decreasing stress, and varicocele repair. The high prevalence of obesity and metabolic syndrome in the United States suggests that disease modification could represent a viable treatment approach for affected men with hypogonadism. CONCLUSIONS These alternatives to TTh can increase testosterone levels and should be considered before TTh. Lo EM, Rodriguez KM, Pastuszak AW, Khera M. Alternatives to Testosterone Therapy: A Review. Sex Med Rev 2018;6:106-113.
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5.
Current medical management of endocrine-related male infertility.
Ring, JD, Lwin, AA, Köhler, TS
Asian journal of andrology. 2016;(3):357-63
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Abstract
Male factor contributes to 50%-60% of overall infertility but is solely responsible in only 20% of couples. Although most male factor infertility is ascertained from an abnormal semen analysis, other male factors can be contributory especially if the sample returns normal. Male infertility can be due to identifiable hormonal or anatomical etiologies that may be reversible or irreversible. This manuscript will highlight existing guidelines and our recommendations for hormone evaluation for male infertility and empiric therapies including multivitamins, estrogen receptor modulators (clomiphene), estrogen conversion blockers (anastrozole), and hormone replacement.
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Ovulation induction in polycystic ovary syndrome: Current options.
Legro, RS
Best practice & research. Clinical obstetrics & gynaecology. 2016;:152-159
Abstract
There are a variety of effective treatment options to induce ovulation in women with polycystic ovary syndrome (PCOS). The most effective treatments are primarily reproductive and target the hypothalamic-pituitary-ovarian (HPO) axis. Letrozole, an aromatase inhibitor, is headed toward replacing clomiphene, a selective estrogen receptor modulator, as the first-choice option. Metabolic treatments likely work indirectly through the HPO axis. Many metabolic treatments have shown initial promise and later failed (troglitozone or d-chiro-inositol) or disappointed (metformin); further studies are needed of newer agents to treat type 2 diabetes. Weight loss interventions, lifestyle related, through obesity drugs or through bariatric surgery have shown mixed results on pregnancy outcomes. With both reproductive and metabolic treatments, combination therapies (such as metformin and clomiphene together) may offer greater benefit to distinct subgroups of patients.
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Relationship Between Breast Density and Selective Estrogen-Receptor Modulators, Aromatase Inhibitors, Physical Activity, and Diet: A Systematic Review.
Ekpo, EU, Brennan, PC, Mello-Thoms, C, McEntee, MF
Integrative cancer therapies. 2016;(2):127-44
Abstract
Background Lower breast density (BD) is associated with lower risk of breast cancer and may serve as a biomarker for the efficacy of chemopreventive strategies. This review explores parameters that are thought to be associated with lower BD. We conducted a systematic review of articles published to date using the PRISMA strategy. Articles that assessed change in BD with estrogen-receptor modulators (tamoxifene [TAM], raloxifene [RLX], and tibolone) and aromatase inhibitors (AIs), as well as cross-sectional and longitudinal studies (LSs) that assessed association between BD and physical activity (PA) or diet were reviewed. Results Ten studies assessed change in BD with TAM; all reported TAM-mediated BD decreases. Change in BD with RLX was assessed by 11 studies; 3 reported a reduction in BD. Effect of tibolone was assessed by 5 RCTs; only 1 reported change in BD. AI-mediated BD reduction was reported by 3 out of 10 studies. The association between PA and BD was assessed by 21 studies; 4 reported an inverse association. The relationship between diet and BD was assessed in 34 studies. All studies on calcium and vitamin D as well as vegetable intake reported an inverse association with BD in premenopausal women. Two RCTs demonstrated BD reduction with a low-fat, high-carbohydrate intervention. Conclusion TAM induces BD reduction; however, the effect of RLX, tibolone, and AIs on BD is unclear. Although data on association between diet and BD in adulthood are contradictory, intake of vegetables, vitamin D, and calcium appear to be associated with lower BD in premenopausal women.
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Pause menopause with Rhodiola rosea, a natural selective estrogen receptor modulator.
Gerbarg, PL, Brown, RP
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2016;(7):763-9
Abstract
BACKGROUND Menopausal women are challenged by the adverse effects of estrogen loss on energy, mood, cognitive function, and memory. These stresses are compounded by increased risks for cardiovascular disease, osteoporosis, and cancer. Known to have neuroprotective, cardio-protective, anti-oxidative and anti-carcinogenic effects, Rhodiola rosea extracts have also been shown to improve energy, mood, cognitive function and memory. PURPOSE We propose that R. rosea be investigated for use as a potential selective estrogen receptor modulator (SERM) in the prevention and treatment of menopause-related fatigue, stress, depression, cognitive decline, memory impairment, cardiovascular disease, osteoporosis and cancer. METHOD This paper briefly reviews the relationship between estrogen decline and menopause-related health risks, the molecular mechanisms underlying estrogenic effects on health, and the evidence indicating beneficial effects of R. rosea extracts on these mechanisms and health risks. Mechanisms include non-genomic and genomic effects, for example: activation of intra-cellular signal transduction pathways by binding to estrogen receptors, ERα-mediated activation of endothelial nitric oxide synthase with increased nitric oxide release; and anti-inflammatory effects, counteracting TNFα by inhibiting nuclear factor-Kappa-B (NF-KB) and protection of osteoblasts from hydrogen peroxide. A clinical case illustrating treatment of a menopausal woman with R. rosea is presented. Risks, benefits, gaps in knowledge, and future directions are discussed. CONCLUSION Numerous lines of evidence indicate that R. rosea should be investigated as a potential selective estrogen receptor modulator (SERM) to prevent, delay or mitigate menopause-related cognitive, psychological, cardiovascular and osteoporotic conditions.
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[Current advances and issues in selective estrogen receptor modulator (SERM) treatment].
Ohta, H
Clinical calcium. 2014;(1):45-52
Abstract
The use of selective estrogen receptor modulators (SERMs) was limited at first to relatively young women and was overestimated for the risk of venous thromboembolism (VTE) due to their estrogen-like effects. Ten years of clinical experience with the SERMs in Japan suggest that they can be used without concern for VTE and are efficacious in older women. Thus, the SERMs are now being recognized as agents readily available for clinical use. Furthermore, unlike the bisphosphonates, their physiological hormone-like effects have led to their widespread use in clinical settings. Future issues in treatment with the SERMs include generation of evidence for their efficacy in improving bone quality as well as for their efficacy in the oldest population. Given their excellent, well-balanced efficacy and safety profile as well as their convenience, however, the SERMs are thought likely to become further established as the standard of care in osteoporosis and other diseases.
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Novel off-target effect of tamoxifen--inhibition of acid ceramidase activity in cancer cells.
Morad, SA, Levin, JC, Tan, SF, Fox, TE, Feith, DJ, Cabot, MC
Biochimica et biophysica acta. 2013;(12):1657-64
Abstract
Acid ceramidase (AC), EC 3.5.1.23, a lysosomal enzyme, catalyzes the hydrolysis of ceramide to constituent sphingoid base, sphingosine, and fatty acid. Because AC regulates the levels of pro-apoptotic ceramide and mitogenic sphingosine-1-phosphate, it is considered an apt target in cancer therapy. The present study reveals, for the first time, that the prominent antiestrogen, tamoxifen, is a pan-effective AC inhibitor in the low, single digit micromolar range, as demonstrated in a wide spectrum of cancer cell types, prostate, pancreatic, colorectal, and breast. Prostate cancer cells were chosen for the detailed investigations. Treatment of intact PC-3 cells with tamoxifen produced time- and dose-dependent inhibition of AC activity. Tamoxifen did not impact cell viability nor did it inhibit AC activity in cell-free assays. In pursuit of mechanism of action, we demonstrate that tamoxifen induced time-, as early as 5min, and dose-dependent, as low as 5μM, increases in lysosomal membrane permeability (LMP), and time- and dose-dependent downregulation of AC protein expression. Assessing various protease inhibitors revealed that a cathepsin B inhibitor blocked tamoxifen-elicited downregulation of AC protein; however, this action failed to restore AC activity unless assayed in a cell-free system at pH4.5. In addition, pretreatment with tamoxifen inhibited PC-3 cell migration. Toremifene, an antiestrogen structurally similar to tamoxifen, was also a potent inhibitor of AC activity. This study reveals a new, off-target action of tamoxifen that may be of benefit to enhance anticancer therapies that either incorporate ceramide or target ceramide metabolism.