The role of estrogen and androgen receptors in bone health and disease
TL;DR: Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR.
Abstract: Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis.
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TL;DR: A comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis is provided.
Abstract: Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution.
481 citations
TL;DR: The remodelling process and its regulation is described, osteoporosis is discussed and the commonest pharmacological interventions used in its management are summarized.
Abstract: The bone remodelling cycle replaces old and damaged bone and is a highly regulated, lifelong process essential for preserving bone integrity and maintaining mineral homeostasis. During the bone remodelling cycle, osteoclastic resorption is tightly coupled to osteoblastic bone formation. The remodelling cycle occurs within the basic multicellular unit and comprises five co-ordinated steps; activation, resorption, reversal, formation and termination. These steps occur simultaneously but asynchronously at multiple different locations within the skeleton. Study of rare human bone disease and animal models have helped to elucidate the cellular and molecular mechanisms that regulate the bone remodelling cycle. The key signalling pathways controlling osteoclastic bone resorption and osteoblastic bone formation are receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin and canonical Wnt signalling. Cytokines, growth factors and prostaglandins act as paracrine regulators of the cycle, whereas endocrine regulators include parathyroid hormone, vitamin D, calcitonin, growth hormone, glucocorticoids, sex hormones, and thyroid hormone. Disruption of the bone remodelling cycle and any resulting imbalance between bone resorption and formation leads to metabolic bone disease, most commonly osteoporosis. The advances in understanding the cellular and molecular mechanisms underlying bone remodelling have also provided targets for pharmacological interventions which include antiresorptive and anabolic therapies. This review will describe the remodelling process and its regulation, discuss osteoporosis and summarize the commonest pharmacological interventions used in its management.
311 citations
Cites background from "The role of estrogen and androgen r..."
...While both osteoblastic bone formation and osteoclastic bone resorption are increased, uncoupling results in resorption outweighing formation.(132)...
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TL;DR: The goal of this Review is to describe in a timely manner new research findings on the global prevalence and physiology of menopausal symptoms and their impact on future health.
Abstract: The symptoms of menopause can be distressing, particularly as they occur at a time when women have important roles in society, within the family and at the workplace Hormonal changes that begin during the menopausal transition affect many biological systems Accordingly, the signs and symptoms of menopause include central nervous system-related disorders; metabolic, weight, cardiovascular and musculoskeletal changes; urogenital and skin atrophy; and sexual dysfunction The physiological basis of these manifestations is emerging as complex and related, but not limited to, oestrogen deprivation Findings generated mainly from longitudinal population studies have shown that ethnic, geographical and individual factors affect symptom prevalence and severity Moreover, and of great importance to clinical practice, the latest research has highlighted how certain menopausal symptoms can be associated with the onset of other disorders and might therefore serve as predictors of future health risks in postmenopausal women The goal of this Review is to describe in a timely manner new research findings on the global prevalence and physiology of menopausal symptoms and their impact on future health
284 citations
TL;DR: Estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues.
Abstract: Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs. 17β-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs. Early studies showed E2 binding in numerous male tissues, and ESR1 and ESR2 each show unique distributions and actions in males. Exogenous estrogen treatment produced male reproductive pathologies in laboratory animals and men, especially during development, and studies with transgenic mice with compromised estrogen signaling demonstrated an E2 role in normal male physiology. Efferent ductules and epididymal functions are dependent on estrogen signaling through ESR1, whose loss impaired ion transport and water reabsorption, resulting in abnormal sperm. Loss of ESR1 or aromatase also produces effects on nonreproductive targets such as brain, adipose, skeletal muscle, bone, cardiovascular, and immune tissues. Expression of GPER is extensive in male tracts, suggesting a possible role for E2 signaling through this receptor in male reproduction. Recent evidence also indicates that membrane ESR1 has critical roles in male reproduction. Thus estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues.
278 citations
TL;DR: It is proposed that estrogens influence fracture risk in aging men via direct effects on bone, whereas androgens exert an additional antifracture effect mainly via extraskeletal parameters such as muscle mass and propensity to fall.
Abstract: Sex steroids are chief regulators of gender differences in the skeleton, and male gender is one of the strongest protective factors against osteoporotic fractures. This advantage in bone strength relies mainly on greater cortical bone expansion during pubertal peak bone mass acquisition and superior skeletal maintenance during aging. During both these phases, estrogens acting via estrogen receptor-α in osteoblast lineage cells are crucial for male cortical and trabecular bone, as evident from conditional genetic mouse models, epidemiological studies, rare genetic conditions, genome-wide meta-analyses, and recent interventional trials. Genetic mouse models have also demonstrated a direct role for androgens independent of aromatization on trabecular bone via the androgen receptor in osteoblasts and osteocytes, although the target cell for their key effects on periosteal bone formation remains elusive. Low serum estradiol predicts incident fractures, but the highest risk occurs in men with additionally low T and high SHBG. Still, the possible clinical utility of serum sex steroids for fracture prediction is unknown. It is likely that sex steroid actions on male bone metabolism rely also on extraskeletal mechanisms and cross talk with other signaling pathways. We propose that estrogens influence fracture risk in aging men via direct effects on bone, whereas androgens exert an additional antifracture effect mainly via extraskeletal parameters such as muscle mass and propensity to fall. Given the demographic trends of increased longevity and consequent rise of osteoporosis, an increased understanding of how sex steroids influence male bone health remains a high research priority.
234 citations
Cites background or methods from "The role of estrogen and androgen r..."
...In males, cortical bone was transiently reduced when ER was deleted in osteoblast precursors and downstream cells (ER Ob;Prx1 mice) (179, 218), whereas no cortical phenotype was evident when ER was deleted in mature osteoblasts (ER Määttä Ob;Osteocalcin and ER ) (Table 2) (179, 219)....
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...trols, one can come to erroneous conclusions (218)....
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...Although the latter study stated that the osteocalcin-Cre mouse strain used did not have a bone phenotype in itself, this was, as emphasized in a recent review by Manolagas et al (218), not excluded quantitatively....
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...sized in a recent review by Manolagas et al (218), not...
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References
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TL;DR: Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD.
Abstract: Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD
14,646 citations
Journal Article•
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TL;DR: A randomized controlled experiment is designed to test whether access to affordable day care (in the form of subsidies, for example) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired.
Abstract: This pilot aims to better understand the market for childcare in Saudi Arabia – both the supply and demand sides – and to design a randomized controlled experiment to test whether access to affordable day care (in the form of subsidies, for example) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired. In addition, the study seeks to understand the degree to which employment early on in one’s life impacts employment in later stages. The pilot will provide information on the groups of women the experiment should target, appropriate levels for the childcare subsidy, and the quality and current geographic locations of daycare sites. Expected Impact Determine the effects of facilitating childcare access on Saudi women’s employment. PRINCIPAL INVESTIGATORS Boston University Patricia Cortes Harvard University Claudia Goldin Swarthmore College Jennifer Peck
9,609 citations
TL;DR: The effects of OPGL are blocked in vitro and in vivo by OPG, suggesting that OPGl and OPG are key extracellular regulators of osteoclast development.
5,334 citations
TL;DR: The role of Ligand in RECEPTOR TRANSFORMATION and ACTIVATION is studied, as well as the role of serotonin, which plays a role in both transformation and inhibition.
Abstract: INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451 STEROID RECEPTOR SUPERFAMILY . . . . . . . . . . . . . . ... . . ... . . . . . 453 PROTEIN-DNA INTERACTIONS . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . 455 ROLE OF RECEPTOR IN GENE ACTIVATION AND SILENCING ......... 459 Gene Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459 Gene Silencing . . .. . . .. . ... . . . . . . . . . . . . .... . . . . . ...... . . 462 SYNERGISM BETWEEN DIFFERENT CIS-ACTING ELEMENTS 465 ROLE OF LIGAND IN RECEPTOR TRANSFORMATION AND ACTIVATION . 466 Role of Ligand .... . ... . .. . .... . ..... . . ... . .. . . ........ . 466 Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 FACTORS INFLUENCING RECEPTOR ACTIVITY . . . . . . . . . . . . . . . . . . . . 473 Phosphorylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Ligand-Independent Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 Nuclear Transcription Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476 CHROMATIN STRUCTURE AND RECEPTOR ACTION . . . . . . . . . . . . . . . . 479 SUMMARY AND PERSPECTIVES 480
2,960 citations
TL;DR: To establish the prevalence of sarc Openia in older Americans and to test the hypothesis that sarcopenia is related to functional impairment and physical disability in older persons is established.
Abstract: OBJECTIVES: To establish the prevalence of sarcopenia in older Americans and to test the hypothesis that sarcope- nia is related to functional impairment and physical dis- ability in older persons. DESIGN: Cross-sectional survey. SETTING: Nationally representative cross-sectional sur- vey using data from the Third National Health and Nutri- tion Examination Survey (NHANES III). PARTICIPANTS: Fourteen thousand eight hundred eigh- teen adult NHANES III participants aged 18 and older. MEASUREMENTS: The presence of sarcopenia and the relationship between sarcopenia and functional impairment and disability were examined in 4,504 adults aged 60 and older. Skeletal muscle mass was estimated from bioimped- ance analysis measurements and expressed as skeletal mus- cle mass index (SMIskeletal muscle mass/body mass � 100). Subjects were considered to have a normal SMI if their SMI was greater than -one standard deviation above the sex-specific mean for young adults (aged 18-39). Class I sarcopenia was considered present in subjects whose SMI was within -one to -two standard deviations of young adult values, and class II sarcopenia was present in subjects whose SMI was below -two standard deviations of young adult values. RESULTS: The prevalence of class I and class II sarcope- nia increased from the third to sixth decades but remained relatively constant thereafter. The prevalence of class I (59% vs 45%) and class II (10% vs 7%) sarcopenia was greater in the older ( � 60 years) women than in the older men ( P � .001). The likelihood of functional impairment and disability was approximately two times greater in the older men and three times greater in the older women with class II sarcopenia than in the older men and women with a normal SMI, respectively. Some of the associations be- tween class II sarcopenia and functional impairment re- mained significant after adjustment for age, race, body mass index, health behaviors, and comorbidity. CONCLUSIONS: Reduced relative skeletal muscle mass in older Americans is a common occurrence that is signifi- cantly and independently associated with functional im- pairment and disability, particularly in older women. These observations provide strong support for the prevailing view that sarcopenia may be an important and potentially re- versible cause of morbidity and mortality in older persons. J Am Geriatr Soc 50:889-896, 2002.
2,710 citations