Browsing by Subject "Estrogens"

Now showing 1 - 10 of 10
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    Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial
    (The Endocrine Society, 2014-09) Quigley, Charmian A.; Wan, Xiaohai; Garg, Sipi; Kowal, Karen; Cutler, Gordon B. Jr.; Ross, Judith L.; Department of Medicine, IU School of Medicine
    CONTEXT: The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined. OBJECTIVE: The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years. DESIGN: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: The study was conducted at two US pediatric endocrine centers. SUBJECTS: Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset. INTERVENTION(S): Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age. MAIN OUTCOME MEASURES: The main outcome measures for this report were median ages at Tanner breast stage ≥2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed. RESULTS: Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not. CONCLUSIONS: In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome.
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    Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole
    (Elsevier, 2015-07) Ingle, James N.; Kalari, K. R.; Buzdar, Aman U.; Robson, Mark E.; Goetz, Matthew P.; Desta, Zeruesenay; Barman, Poulami; Dudenkov, Tanda T.; Northfelt, Donald W.; Perez, Edith A.; Flockhart, David A.; Williard, Clark V.; Wang, Liewei; Weinshilboum, Richard M.; Department of Medicine, IU School of Medicine
    PURPOSE: We determined hormone concentrations (estradiol [E2], estrone [E1], estrone conjugates [E1-C], androstenedione [A], testosterone [T]) before and on anastrozole therapy where we also determined plasma concentrations of anastrozole and its metabolites. EXPERIMENTAL: Postmenopausal women who were to receive adjuvant anastrozole for resected early breast cancer were studied. Pretreatment, blood samples were obtained for the acquisition of DNA and for plasma hormone measurements (E2, E1, E1-C, A, and T). A second blood draw was obtained at least 4 weeks after starting anastrozole for hormone, anastrozole and metabolite measurements. For hormone assays, a validated bioanalytical method using gas chromatography negative ionization tandem mass spectrometry was used. Anastrozole and metabolite assays involved extraction of plasma followed by LC/MS/MS assays. RESULTS: 649 patients were evaluable. Pretreatment and during anastrozole, there was large inter-individual variability in E2, E1, and E1-C as well as anastrozole and anastrozole metabolite concentrations. E2 and E1 concentrations were below the lower limits of quantitation in 79% and 70%, respectively, of patients on anastrozole therapy, but those with reliable concentrations had a broad range (0.627-234.0 pg/mL, 1.562-183.2 pg/mL, respectively). Considering E2, 8.9% had the same or higher concentration relative to baseline while on anastrozole, documented by the presence of drug. CONCLUSIONS: We demonstrated large inter-individual variability in anastrozole and anastrozole metabolite concentrations as well as E1, E2, E1-C, A, and T concentrations before and while on anastrozole. These findings suggest that the standard 1mg daily dose of anastrozole is not optimal for a substantial proportion of women with breast cancer.
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    Interstrain differences in the development of pyometra after estrogen treatment of rats
    (American Association for Laboratory Animal Science, 2009-09) Brossia, Lisa Jane; Roberts, Christopher Sean; Lopez, Jennifer T.; Bigsby, Robert M.; Dynlacht, Joseph R.; Pharmacology and Toxicology, School of Medicine
    This case report describes the unanticipated development of pyometra in Brown Norway rats after treatment with estrogen. Sprague Dawley and Brown Norway rats were ovariectomized and randomly assigned to treatment groups (subcutaneous implantation of either a capsule containing 20 mg 17beta-estradiol or an empty capsule, as a control). After irradiation of only the right eye, the rats were followed for several months in an attempt to determine the effects of estrogen on radiation cataractogenesis and investigate potential strain differences in this phenomenon. However, all Brown Norway rats that received estradiol treatment developed pyometra, whereas none the Sprague Dawley or control Brown Norway rats did. This case demonstrates the potential adverse effects of exogenous estrogen therapy, which are strain-specific in the rat. Caution should be taken when designing estrogen-related experiments involving Brown Norway rats and other potentially sensitive strains.
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    The microenvironment matters: estrogen deficiency fuels cancer bone metastases
    (American Association for Cancer Research, 2014-06-01) Wright, Laura E.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Factors released during osteoclastic bone resorption enhance disseminated breast cancer cell progression by stimulating invasiveness, growth, and a bone-resorptive phenotype in cancer cells. Postmenopausal bone loss may accelerate progression of breast cancer growth in bone, explaining the anticancer benefit of the bone-specific antiresorptive agent zoledronic acid in the postmenopausal setting. Clin Cancer Res; 20(11); 2817-9. ©2014 AACR.
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    Modifications in Bone Matrix of Estrogen-Deficient Rats Treated with Intermittent PTH
    (Hindawi Publishing Corporation, 2015-01-28) Pacheco-Costa, Rafael; Campos, Jenifer Freitas; Katchburian, Eduardo; de Medeiros, Valquíria Pereira; Nader, Helena Bonciani; Nonaka, Keico Okino; Plotkin, Lilian Irene; Reginato, Rejane Daniele; Department of Anatomy & Cell Biology, IU School of Medicine
    Bone matrix dictates strength, elasticity, and stiffness to the bone. Intermittent parathyroid hormone (iPTH), a bone-forming treatment, is widely used as a therapy for osteoporosis. We investigate whether low doses of intermittent PTH (1-34) change the profile of organic components in the bone matrix after 30 days of treatment. Forty 6-month-old female Wistar rats underwent ovariectomy and after 3 months received low doses of iPTH administered for 30 days: daily at 0.3 µg/kg/day (PTH03) or 5 µg/kg/day (PTH5); or 3 times per week at 0.25 µg/kg/day (PTH025). After euthanasia, distal femora were processed for bone histomorphometry, histochemistry for collagen and glycosaminoglycans, biochemical quantification of sulfated glycosaminoglycans, and hyaluronan by ELISA and TUNEL staining. Whole tibiae were used to estimate the bone mineral density (BMD). Histomorphometric analysis showed that PTH5 increased cancellous bone volume by 6% over vehicle-treated rats. In addition, PTH5 and PTH03 increased cortical thickness by 21% and 20%, respectively. Tibial BMD increased in PTH5-treated rats and this group exhibited lower levels of chondroitin sulfate; on the other hand, hyaluronan expression was increased. Hormonal administration in the PTH5 group led to decreased collagen maturity. Further, TUNEL-positive osteocytes were decreased in the cortical compartment of PTH5 whereas administration of PTH025 increased the osteocyte death. Our findings suggest that daily injections of PTH at low doses alter the pattern of organic components from the bone matrix, favoring the increase of bone mass.
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    Pyk2: Potential Regulator of Post Menopausal Bone Loss
    (2013) Largura, Heather; Liu, Sean S.; Stewart, Kelton T.; Baldwin, James Joseph, 1925-; Allen, Matthew R.; Bruzzaniti, Angela
    Osteoporosis is a pathologic condition of bone, commonly found in post-menopausal women, which occurs from an imbalance between bone formation and resorption. Following menopause, the bone resorbing activity of osteoclasts exceeds bone formation by osteoblasts, resulting in decreased trabecular and cortical bone and a subsequent decrease in bone mass. Reduced bone mass increases the risk of pathologic fracture of bones. Due to adverse effects associated with current treatment protocols for bone loss, alternative treatment modalities with reduced adverse effects are needed. Estrogen plays a role in maintaining balance in the bone remodeling cycle by controlling remodeling activation, osteoblast and osteoclast numbers, and their respective effectiveness in formation and resorption. With declining estrogen levels, this elegantly balanced interaction is altered and bone resorption exceeds bone formation, resulting in bone loss and increased bone fragility. Pyk2 is a protein tyrosine kinase that plays an important role in regulating bone resorption by osteoclasts, as well as osteoblast proliferation and differentiation. Deletion of the Pyk2 gene in mice leads to an increase in bone mass, in part due to dysfunctional osteoclast and osteoblast activity. In this study, we examined the role of Pyk2 in the effects of estrogen on bone mass. We used wild type (WT) and Pyk2 knock-out (KO) mice that had been ovariectomized (OVX) and treated with or without estrogen (E2)-releasing pellets. Control mice included sham OVX surgery receiving placebo pellet. We found that deletion of Pyk2 conferred increased bone mass in sham, OVX and OVX+E2 mice. In addition, Pyk2 KO mice supplemented with 17estradiol exhibited a marked increase in bone volume/trabecular volume, trabecular number, and trabecular thickness, but not cortical bone parameters compared to WT mice. Results of this study provide evidence for the role of Pyk2 in the effects of estrogen on bone mass. Understanding the role of Pyk2 in bone could lead to the development of new pharmaceutical targets for the treatment of bone loss associated with osteoporosis.  
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    Regulation of osteoblast activity by Pyk2-targeted approaches
    (2016-11-15) Posritong, Sumana; Bruzzaniti, Angela; Chu, Tien-Min G.; Bottino, Marco C.; Li, Jiliang; Main, Russell P.
    The hormonal and cellular mechanisms controlling bone formation are not completely understood. The proline-rich tyrosine kinase 2 (Pyk2) is important for osteoblast (OB) activity and bone formation. However, female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone volume/total volume. Previously, our laboratory found ovariectomized Pyk2-KO mice supplemented with 17β-estradiol (E2) exhibited a greater increase in bone volume than WT mice treated with E2. The overall hypotheses of our studies are that Pyk2 regulates OB activity by modulating the E2-signaling cascade and that a Pyk2-inhibitor will promote OB activity and be suitable for bone regeneration applications. In Aim1, we determined the mechanism of action of Pyk2 and E2 in OBs. Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In the presence of E2 or raloxifene, a selective estrogen receptor (ER) modulator, both matrix formation and mineralization were further increased in Pyk2-KO OBs, but not WT OBs. Consistent with a role of Pyk2 in E2 signaling, Pyk2-depletion led to the proteasome-mediated degradation of ERα, but not ERβ. Finally, we found Pyk2-depletion and E2 have an additive effect on ERK phosphorylation, known to increase cell differentiation and survival. In Aim2, we developed a Pyk2-inhibitor loaded hydrogel and evaluated its viscosity, gelation time, swelling, degradation, and release behavior. We found that a hydrogel composed of PEGDA1000 plus 10% gelatin exhibited viscosity and shear-thinning behavior suitable for use as an injectable-carrier. Importantly, the Pyk2-inhibitor-hydrogel was cytocompatible, retained its inhibitory activity against Pyk2 leading to an increase in OB activity. In conclusion, therapeutic strategies targeting Pyk2 may improve systemic bone formation, while Pyk2-inhibitor loaded hydrogels may be suitable for targeted bone regeneration in craniofacial and/or the other skeletal defects.
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    Sex-Dependent Differences in Cholestasis: Why Estrogen Signaling May Be a Key Pathophysiological Driver
    (Elsevier, 2023) Ismail, AbdiGhani; Kennedy, Lindsey; Francis, Heather; Medicine, School of Medicine
    Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are cholestatic liver diseases that have significant clinical impact with debilitating symptoms and mortality. While PBC is predominantly seen in perimenopausal and postmenopausal women, men who are diagnosed with PBC have worse clinical outcomes and all-cause mortality. In contrast, 60% to 70% of patients with PSC are men; the data indicate that female sex may be an independent factor against PSC-related complications. These findings suggest a sex-dependent biological basis for these differences. Estrogen has been implicated in the pathogenesis of intrahepatic cholestasis of pregnancy and may induce cholestasis through a variety of interactions. However, it is unclear why some sexual dimorphic features may provide a protective effect despite known estrogen models that induce cholestasis. This article provides a brief introductory background and discusses the sexual dimorphism in clinical presentation in PSC and PBC. It also explores the role of estrogen signaling in pathogenesis and how it relates to intrahepatic cholestasis of pregnancy. Studies have already targeted certain molecules involved in estrogen signaling, and this review discusses these studies that identify estrogen-related receptor, estrogen receptor-α, estrogen receptor-β, farnesoid X receptor, and mast cells as possible targets, in addition to long noncoding RNA H19-induced cholestasis and sexual dimorphism. It also explores these interactions and their role in the pathogenesis of PBC and PSC.
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    Sexual Dimorphism in the Musculoskeletal System: Sex Hormones and Beyond
    (Oxford University Press, 2024-09-01) Plotkin, Lilian I.; Bruzzaniti, Angela; Pianeta, Roquelina; Anatomy, Cell Biology and Physiology, School of Medicine
    Mounting evidence indicates that whereas some fundamental aspects of bone cell differentiation and function are similar in females and males, there is a clear contribution of sex/gender on the effects of signaling molecules on bone mass and strength and, consequently, on the effects of pharmacologic approaches to treat skeletal disorders. However, until recently, most studies were designed and performed using only 1 sex, resulting in a scarcity of published information on sexual dimorphism of the musculoskeletal system, including the mandible/masticatory muscles and the axial and appendicular bones and skeletal muscles. Further, it is now recognized that scientific rigor requires the study of both males and females. Therefore, there is an increasing need to understand the molecular and cellular basis for the differential outcomes of genetic manipulations and therapeutic agent administration depending on the sex of the experimental animals. Studies have shown higher muscle mass, cancellous bone mass, and long bone width in males compared with females as well as different traits in the pelvis and the skull, which are usually used for gender identification in forensic anthropology. Yet, most reports focus on the role of sex hormones, in particular, the consequences of estrogen deficiency with menopause in humans and in ovariectomized animal models. In addition, emerging data is starting to unveil the effects of gender-affirming hormonal therapy on the musculoskeletal system. We summarize here the current knowledge on the sex/gender-dependent phenotypic characteristics of the bone and skeletal muscles in humans and rodents, highlighting studies in which side by side comparisons were made.