RESUMO
Prolonged critically ill patients present with distinct alterations in calcium and bone metabolism. Circulating bone formation markers are reduced and bone resorption markers are substantially elevated, indicating an uncoupling between osteoclast and osteoblast activity, possibly resulting in pronounced bone loss, impaired traumatic or surgical fracture healing, and osteoporosis. In addition, we have previously shown that increased circulating osteoclast precursors in critically ill patients result in increased osteoclastogenesis in vitro, possibly through FcγRIII signaling. In the current study, we investigated the effects of sustained critical illness on bone metabolism at the tissue level in a standardized rabbit model of prolonged (7 days), burn injury-induced critical illness. This in vivo model showed a reduction in serum ionized calcium and osteocalcin levels, as is seen in humans. Trabecular area, bone mineral content, and -density were decreased in sick rabbits [by 43% (p<0.01), 31% (p<0.01), and 29% (p<0.05), respectively], as was the trabecular gene expression of osteoblast and angiogenesis markers, indicating decreased bone formation and impaired vascularization. There was no change in the expression of osteoclast differentiation markers from the canonical RANK/RANKL/OPG pathway, however, there was an increase in expression of markers from the non-canonical, immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway, FcγRIII, and DAP12 (148% and 59%, respectively; p<0.01). The current study has shown a detrimental effect of prolonged critical illness on trabecular bone integrity, possibly explained by reduced osteoblast differentiation and angiogenesis, coupled with increased osteoclastogenesis signaling that may be mediated via the non-canonical immunoreceptor tyrosine-based activation motif signaling pathway.
Assuntos
Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Estado Terminal , Motivo de Ativação do Imunorreceptor Baseado em Tirosina , Animais , Biomarcadores/metabolismo , Reabsorção Óssea/sangue , Reabsorção Óssea/genética , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cálcio/sangue , Regulação da Expressão Gênica , Humanos , Íons/sangue , Masculino , Neovascularização Fisiológica/genética , Osteocalcina/sangue , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/genética , Coelhos , Transdução de SinaisRESUMO
OBJECTIVE: To design a trisomy 21 screening protocol for sequential triage in the first trimester, and to evaluate whether it reduces the need for advanced ultrasound scanning to such an extent that this could be dealt with by a limited number of well-trained sonographers only. METHODS: Screening results of 31 trisomy 21 affected pregnancies and 16 096 unaffected pregnancies from the first trimester screening program of Algemeen Medisch Laboratorium in Antwerp, Belgium, were used to define high-risk, intermediate-risk and low-risk groups. A serum screening result (age, pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG)) of >or=1 : 30 and/or a nuchal translucency thickness (NT) measurement of >or= 3.5 mm were classified as high risk. A serum screening result of < 1 : 1000 together with an NT of < 3.5 mm were classified as low risk. Other results were considered intermediate risk, for which further advanced ultrasound screening would be indicated. This protocol was then evaluated prospectively in another population of 13 493 first-trimester pregnancies. RESULTS: Of the total population, 1.9% was identified as being high risk (14 trisomy 21 pregnancies and 222 unaffected pregnancies; prevalence, 1 : 17), 59.6% was identified as being low risk (three trisomy 21 pregnancies and 9615 unaffected pregnancies; prevalence, 1 : 3206) and 38.4% was identified as being intermediate risk (10 trisomy 21 pregnancies and 6190 unaffected pregnancies; prevalence, 1 : 620). A similar distribution was found in the prospective arm of the study. There was no reduction of overall screening performance compared with our current first-trimester combined screening program. The number of intermediate-risk pregnancies was sufficiently low as to enable advanced ultrasound scanning by well-trained sonographers only. CONCLUSION: In population screening for fetal trisomy 21, sequential triage in the first trimester can be achieved using very simple methods. Pregnancies at high or at low risk can be identified easily and the number of pregnancies at intermediate risk can be reduced sufficiently to enable advanced ultrasound scanning by well-trained sonographers only. A prospective study is needed to evaluate the performance of this approach and to compare its results with current combined or integrated screening algorithms.
Assuntos
Síndrome de Down/diagnóstico , Doenças Fetais/diagnóstico , Diagnóstico Pré-Natal/métodos , Adulto , Biomarcadores/sangue , Gonadotropina Coriônica Humana Subunidade beta/sangue , Protocolos Clínicos , Síndrome de Down/diagnóstico por imagem , Feminino , Doenças Fetais/diagnóstico por imagem , Humanos , Programas de Rastreamento/métodos , Seleção de Pacientes , Gravidez , Primeiro Trimestre da Gravidez , Proteína Plasmática A Associada à Gravidez/análise , Estudos Prospectivos , Medição de Risco/métodos , Ultrassonografia Pré-NatalRESUMO
OBJECTIVES: To audit nuchal translucency thickness (NT) measurements for fetal aneuploidy screening in Flanders, and to estimate the impact of small variations in NT measurement on the screening result of two first-trimester screening algorithms: maternal age + NT (Algorithm A), and maternal age + NT + pregnancy associated plasma protein-A + free beta-human chorionic gonadotropin (Algorithm B). METHODS: We used the database of first-trimester combined screening, as collected by the General Medical Laboratory AML in Antwerp, Belgium, between 1 January 2001 and 1 April 2004. Audit was performed by establishing a delta-NT distribution curve for one trainee of The Fetal Medicine Foundation (FMF) and for a group of 263 other sonographers, in comparison with the FMF reference values. Risks for fetal aneuploidy were calculated at a cut-off value of 1 : 300 for Algorithm A and 1 : 150 for Algorithm B. These risks were recalculated in both algorithms after a modeled increase of all NT values by 0.1 or 0.2 mm. RESULTS: In a total of 592 measurements performed by the FMF trainee, the 5th, 50th and 95th percentiles of delta-NT measurements were at -0.41, +0.03 and +0.68 mm, respectively. These values were close to the FMF reference values. The screen-positive rate for this set of data was 4.4% (26/592) in both algorithms. For the 12 555 measurements of the 263 other sonographers, the 5th, 50th and 95th percentiles of delta-NT were at -0.81, -0.14 and +0.73 mm, respectively, which clearly indicates underestimation of NT in the lower range. In this set of data the screen-positive rate was 3.5% for both algorithms (439/12 555 for Algorithm A and 436/12 555 for Algorithm B). Also in this group, 5% (59/1186) of negative screening results at maternal age > or = 35 years in Algorithm A became positive after a modeled 0.1-mm increase in NT, whereas this was only in 1.2% (134/11 369) of tests at maternal age < 35 years (P < 0.0001). The overall increase of screen-positive rate in Algorithm A after an NT modification of +0.1 mm was 1.2% (152/12 555), significantly more than in Algorithm B (86/12 555; 0.7%) (P < 0.0001). CONCLUSION: In Flanders, there is a systematic underestimation of NT in comparison with the FMF reference range. Attempts to change these measurements according to the FMF criteria are crucial. This will mainly influence the screening results of women at advanced maternal age and of NT-based algorithms without the use of other parameters.
Assuntos
Medição da Translucência Nucal/normas , Trissomia , Adulto , Estatura Cabeça-Cóccix , Feminino , Humanos , Idade Materna , Auditoria Médica , Gravidez , Primeiro Trimestre da Gravidez , Padrões de ReferênciaRESUMO
UNLABELLED: 1alpha,25(OH)2-vitamin D strongly regulates the expression of the epithelial calcium channel CaT1. CaT1 expression is reduced in ERKOalpha mice and induced by estrogen treatment, pregnancy, or lactation in VDR WT and KO mice. Estrogens and vitamin D are thus independent potent regulators of the expression of this calcium influx mechanism, which is involved in active intestinal calcium absorption. INTRODUCTION: Active duodenal calcium absorption consists of three major steps: calcium influx into, transfer through, and extrusion out of the enterocyte. These steps are carried out by the calcium transport protein 1 (CaT1), calbindin-D9K, and the plasma membrane calcium ATPase (PMCA1b), respectively. We investigated whether estrogens or hormonal changes during the female reproductive cycle influence the expression of these genes, and if so, whether these effects are vitamin D-vitamin D receptor (VDR) dependent. MATERIALS AND METHODS: We evaluated duodenal expression patterns in estrogen receptor (ER)alpha and -beta knockout (KO) mice, as well as in ovariectomized, estrogen-treated, pregnant, and lactating VDR wild-type (WT) and VDR KO mice. RESULTS: Expression of calcium transporter genes was not altered in ERKObeta mice. CaT1 mRNA expression was reduced by 55% in ERKOalpha mice, while the two other calcium transporter genes were not affected. Ovariectomy caused no change in duodenal expression pattern of VDR WT and KO mice, whereas treatment with a pharmacologic dose of estrogens induced CaT1 mRNA expression in VDR WT (4-fold) and KO (8-fold) mice. Pregnancy enhanced CaTI expression equally in VDR WT and KO mice (12-fold). Calbindin-D9K and PMCA1b expression increased to a lesser extent and solely in pregnant VDR WT animals. In lactating VDR WT and KO mice, CaT1 mRNA expression increased 13 times, which was associated with a smaller increase in calbindin-D9K protein content and PMCA1b mRNA expression. CONCLUSIONS: Estrogens or hormonal changes during pregnancy or lactation have distinct, vitamin D-independent effects at the genomic level on active duodenal calcium absorption mechanisms, mainly through a major upregulation of the calcium influx channel CaT1. The estrogen effects seem to be mediated solely by ERalpha.
Assuntos
Canais de Cálcio/fisiologia , Cálcio/metabolismo , Estrogênios/metabolismo , Receptores de Calcitriol/metabolismo , Regulação para Cima , Animais , Transporte Biológico , Enterócitos/metabolismo , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Camundongos , Camundongos Knockout , Modelos Genéticos , Mutagênese , RNA Mensageiro/metabolismo , Receptores de Estrogênio/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Canais de Cátion TRPV , Vitamina D/metabolismoRESUMO
The objective of this study was to document the occurrence and to correlate the prevalence of different human papillomavirus (HPV) types with the cytological results on simultaneously performed thin-layer preparations in a large population of Flemish women. During 1 year, 69 290 thin-layer preparations were interpreted using the Bethesda classification system. Using an algorithm for HPV testing based on consensus primers and type-specific PCRs in combination with liquid-based cytology, we determined the occurrence and distribution of 14 different oncogenic HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68). Reflex HPV testing was performed on cytologically abnormal samples and on an age matched randomly selected control group with normal cervical cytology (n=1351). Correlation between cytology, age and prevalence for the 14 different high-risk HPV types is given. There is a significant increase in predominance of high-risk HPV types, with increasing abnormal cytology. Coinfection with multiple HPV types also increased with cytological abnormalities, and was highest in HSIL (16.7%). In Flanders, HSIL was most often associated with HPV types 16, 33, 35, 31, 18 and 51. Using thin-layer liquid-based cytology and PCR to detect HPV, it is feasible to screen large numbers of women.
Assuntos
Técnicas Citológicas/métodos , DNA Viral/análise , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase/métodos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bélgica/epidemiologia , Colo do Útero/patologia , Colo do Útero/virologia , DNA Viral/genética , Feminino , Humanos , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/patologia , Prevalência , Fatores de RiscoRESUMO
This study was designed to evaluate the impact of estrogen versus androgen action on orchidectomy (ORX)-induced bone loss and associated changes in body composition. During an experimental period of 4 months, aged (12-month-old) ORX rats were treated with 17beta-estradiol (E2; 0.75 microg/day) or different doses of the nonaromatizable androgen 5alpha-dihydrotestosterone (DHT; 45, 75, and 150 microg/day, respectively), via subcutaneous (sc) silastic implants. Low doses of DHT and E2 inhibited the ORX-induced rise of bone turnover markers (serum osteocalcin and urinary deoxypyridinoline [DPD]) to a similar extent. High-dose DHT prevented the ORX-induced decrease of trabecular bone density but had no significant effect on cortical thinning as assessed by peripheral quantitative computed tomography (pQCT). This bone-sparing action of DHT occurred at the expense of hypertrophy of the ventral prostate and seminal vesicles. On the other hand, E2 restored both trabecular bone density and cortical thickness in ORX rats and even prevented age-related bone loss. In contrast to DHT, E2 increased lean body mass and inhibited the ORX-associated increase of fat mass, as measured by DXA. Administration of E2 was associated with increased serum concentrations of insulin-like growth factor (IGF) I and decreased circulating levels of leptin. We conclude that, in the aged ORX rat model, E2 is more effective in preventing ORX-induced bone loss than DHT. Additionally, E2 has anabolic effects on muscle tissue and prevents the ORX-related increase of fat mass. Overall, these data suggest that androgen action on bone and body composition is dependent on stimulation of both androgen receptors (ARs) and estrogen receptors (ERs).
Assuntos
Di-Hidrotestosterona/farmacologia , Estradiol/farmacologia , Osteoporose/tratamento farmacológico , Envelhecimento/fisiologia , Anabolizantes/farmacologia , Animais , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Masculino , Orquiectomia , RatosRESUMO
Testosterone (T) can affect bone metabolism not only directly, but also via its metabolites, estrogen or dihydrotestosterone, produced by enzymes present in bone. Therefore, the aim of this study was to investigate whether the high-affinity estrogen receptor ligand ICI 182,780 (ICI) impaired the bone-protective action of T in 3-month-old orchidectomized (Orch) rats, studied during an experimental period of 3 months. As expected, Orch significantly decreased trabecular bone volume in the proximal tibial metaphysis (-52%), as measured by histomorphometry, and had a similar negative effect on volumetric bone mineral density (BMD) in the distal femoral metaphysis (-53%), as assessed by peripheral quantitative computed tomography (pQCT). The loss of bone induced by Orch was completely prevented by T administration. Moreover, the Orch-associated increases of biochemical markers of bone turnover (serum osteocalcin, urinary deoxypyridinoline, and calcium excretion) did not occur when Orch rats received T. Administration of ICI in combination with T did not impair this bone-sparing effect. Cortical bone parameters (as determined by pQCT), body weight gain, and body composition (as measured by dual-energy X-ray absorptiometry) were not affected by T or ICI in combination with T. Furthermore, no differences were observed in serum concentrations of insulin-like growth factor-I or glucose homeostasis. In conclusion, ICI does not impair the long-term bone-protective effects of T in orchidectomized male rats, suggesting that testosterone can mediate its effect on the male skeleton directly via the androgen receptor. The absence of effects on body growth via the growth hormone--insulin-like growth factor-I axis may be a possible explanation for the lack of skeletal effects of this selective estrogen receptor antagonist.
Assuntos
Osso e Ossos/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Receptores de Estrogênio/metabolismo , Testosterona/farmacologia , Animais , Biomarcadores/análise , Osso e Ossos/metabolismo , Interações Medicamentosas , Estradiol/metabolismo , Antagonistas de Estrogênios/farmacologia , Estrogênios/metabolismo , Seguimentos , Fulvestranto , Ligantes , Masculino , Modelos Animais , Orquiectomia/efeitos adversos , Ratos , Ratos Wistar , Receptores Androgênicos/metabolismo , Testosterona/metabolismoRESUMO
To examine the role of the estrogen receptor-alpha (ERalpha) during male skeletal development, bone density and structure of aged ERalphaKO mice and wild-type (WT) littermates were analyzed and skeletal changes in response to sex steroid deficiency and replacement were also studied. In comparison to WT, ERalphaKO mice had smaller and thinner bones, arguing for a direct role of ERalpha to obtain full skeletal size in male mice. However, male ERalphaKO mice had significantly more trabecular bone as assessed both by pQCT and histomorphometry, indicating that ERalpha is not essential to maintain cancellous bone mass. Six weeks following orchidectomy (ORX), both WT and ERalphaKO mice showed high-turnover osteoporosis as revealed by increases in serum osteocalcin and decreases in trabecular (-38% and -58% in WT and ERalphaKO, respectively) and cortical bone density (-5% and -4% in WT and ERalphaKO, respectively). Administration of testosterone propionate (T, 5 mg/kg/day) completely prevented bone loss both in ERalphaKO and in WT mice. As expected, estradiol (E2, 60 microg/kg/day) replacement did not prevent cancellous bone loss in ORX ERalphaKO mice. However, E2 stimulated bone formation at the endocortical surface in ORX ERalphaKO, suggesting that osteoblasts may respond to nonERalpha-mediated estrogen action. In conclusion, although functional ERalpha may play a significant role during male skeletal development, this receptor does not seem essential for androgen-mediated skeletal maintenance in older male mice.
Assuntos
Orquiectomia/efeitos adversos , Osteoporose/prevenção & controle , Receptores de Estrogênio/fisiologia , Testosterona/farmacologia , Animais , Densidade Óssea , Receptor alfa de Estrogênio , Masculino , Camundongos , Camundongos Knockout , Osteoporose/etiologia , Receptores de Estrogênio/genéticaRESUMO
Aromatization of androgens into estrogens may be important for maintenance of the male skeleton. To address this hypothesis, we evaluated the skeletal effects of selective estrogen deficiency as induced by the aromatase inhibitor vorozole (Vor), with or without 17beta-estradiol (E(2)) administration (1.35 microg/day), in aged (12-month-old) male rats. A baseline group was killed at the start of the experiment (Base). The control group (Control), the group treated with vorozole alone (Vor), the group treated with E(2) alone (E(2)), or the group with a combination of both (Vor + E(2)) were killed 15 weeks later. Vorozole significantly increased serum testosterone (T) and reduced serum E(2) compared with Control. Body weight gain and serum insulin-like growth factor-I (IGF-I) were also lower in Vor, whereas significant weight loss and decrease of serum IGF-I occurred as a result of E(2) administration. Bone formation as assessed by serum osteocalcin was unaffected but osteoid surface in the proximal metaphysis of the tibia was increased in Vor-treated rats. Bone resorption as evaluated by urinary deoxypyridinoline excretion was increased in Vor. Biochemical parameters of bone turnover were reduced significantly in all E(2) treated rats. Premature closure of the growth plates and decreased osteoid and mineralizing surfaces were also observed in E(2) and Vor + E(2). Apparent bone density of lumbar vertebrae and femur, as measured by dual-energy X-ray absorptiometry (DXA), was significantly reduced in Vor. Vorozole decreased femoral bone density mainly in the distal femur (trabecular and cortical region). This decrease of bone density was not present in E(2) and Vor + E(2). Similar findings were observed when bone density was assessed by peripheral quantitative computed tomography (pQCT); that is, trabecular density of the distal femur, the proximal tibia, and the distal lumbar vertebra were all lower in Vor. This decrease in density was not observed in all E(2)-treated animals. In conclusion, administration of the aromatase inhibitor, vorozole, to aged male rats induces net trabecular bone loss in both the appendicular and axial skeleton, despite a concomitant increase in serum testosterone. E(2) administration is able to prevent this trabecular bone loss in vorozole-treated animals.
Assuntos
Envelhecimento , Inibidores da Aromatase , Osso e Ossos/fisiopatologia , Inibidores Enzimáticos/farmacologia , Estrogênios/deficiência , Triazóis/farmacologia , Animais , Peso Corporal , Densidade Óssea , Remodelação Óssea , Estradiol/administração & dosagem , Masculino , Modelos Animais , Ratos , Ratos WistarRESUMO
The aim of this study was to evaluate the additional value of dimeric inhibin-A serum concentration in second trimester multiple-marker screening tests for pregnancies affected by Down's syndrome. We anticipated that second trimester maternal serum dimeric inhibin-A concentrations would be altered in pregnancies complicated by fetal Down's syndrome and that dimeric inhibin-A would perform better than one of the three substances analysed in the multiple-marker screening test currently in use. A total of 1156 serum samples were screened for dimeric inhibin-A in parallel with the routine classic triple test screening programme performed on a random obstetric population. Classic triple test performance was compared with detection rates obtained after substitution of unconjugated oestriol by inhibin-A and with the performance of inhibin-A and alpha-fetoprotein alone. Absolute dimeric inhibin-A maternal serum concentrations of Down's syndrome pregnancies were indeed significantly higher than those of normal pregnancies in our screened population. The performance of dimeric inhibin-A in combination with the multiple-marker screening test, however, is limited because of its strong correlation with intact human chorionic gonadotrophin.
Assuntos
Biomarcadores , Síndrome de Down/sangue , Inibinas/sangue , Diagnóstico Pré-Natal , Algoritmos , Gonadotropina Coriônica Humana Subunidade beta/sangue , Dimerização , Estriol/sangue , Reações Falso-Positivas , Feminino , Humanos , Gravidez , Segundo Trimestre da Gravidez , Valores de Referência , alfa-Fetoproteínas/análiseRESUMO
Levels of inhibin A and B as well as other hormones in serum samples obtained during the pill-free interval in women taking combined oral contraceptives (OC) were measured to asses the extent of ovarian activity during that period. Type of pill and day of pill-free interval were recorded during routine gynecologic check-ups, if patients were in the pill-free period and had taken their pills regularly in the previous cycle. In addition to inhibin A and B, serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone were also quantified. Inhibin B levels rise significantly in parallel with rising levels of FSH, LH, and E2. Progesterone levels were completely suppressed and inhibin A levels rose slightly but insignificantly. Inhibins are sensitive biochemical markers of ovarian activity in pill-free intervals.
PIP: Serum values of dimeric inhibin A and B were measured to assess the restoration of pituitary and ovarian activity during the pill-free interval in women taking combined oral contraceptives. 175 healthy women 18-35 years of age from five areas in Belgium were enrolled and monitored during routine gynecologic examinations. During the 7 day pill-free interval, inhibin B levels rose significantly in parallel with rising levels of follicle-stimulating hormone, luteinizing hormone, and estradiol. Progesterone levels were completely suppressed. Inhibin A levels rose slightly but insignificantly, reflecting an absence of development of preovulatory follicles. These findings indicate that inhibins are sensitive biochemical markers of ovarian activity in pill-free intervals. Inhibin B appears to be predominantly a product of the cohort of developing primary and subsequent early antral follicles, while inhibin A secretion is more indicative of dominant follicular and corpus luteum function.
Assuntos
Congêneres do Estradiol/administração & dosagem , Etinilestradiol/administração & dosagem , Inibinas/sangue , Folículo Ovariano/efeitos dos fármacos , Progestinas/administração & dosagem , Adulto , Biomarcadores/sangue , Estudos de Coortes , Dimerização , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Estradiol/sangue , Estradiol/metabolismo , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/metabolismo , Humanos , Inibinas/química , Inibinas/efeitos dos fármacos , Inibinas/metabolismo , Hormônio Luteinizante/sangue , Hormônio Luteinizante/efeitos dos fármacos , Folículo Ovariano/fisiologia , Progesterona/sangue , Progesterona/metabolismo , Fatores de TempoRESUMO
Aromatization of androgens into estrogens may explain some of the skeletal action of androgens. We examined the effect of the aromatase inhibitor Vorozole (VOR) on skeletal growth and mineral accumulation in growing 6-week-old male Wistar rats. Rats were either Sham-operated (Sham) or Orchidectomized (Orch) and treated with or without the aromatase inhibitor VOR. One Sham-operated group was killed at Baseline (Base); the four other groups (Sham, Sham + VOR, Orch, Orch + VOR) were killed 18 weeks after surgery. As expected, all groups gained body weight, but body weight gain was significantly (-25%) lower in Orch, Orch + VOR, and Sham + VOR. Both bone formation, as assessed by serum osteocalcin, and bone resorption, as assessed by urinary (deoxy)pyridinoline, decreased significantly in all groups compared with Base. Orchidectomy resulted in a relative increase of biochemical markers of bone formation and resorption compared with Sham. Treatment with VOR, however, resulted only in a very moderate increase of (deoxy)pyridinoline compared with Sham. As expected, femoral length increased compared with Base, but orchidectomy reduced the relative growth of the femur whereas VOR did not influence femoral length. Ex vivo, densitometric and geometric properties of the femora were evaluated by peripheral computerized quantitative tomography (pQCT) and dual-energy x-ray absorptiometry (DXA). The lumbar vertebrae were measured by DXA. At the end of the experimental period, volumetric trabecular bone mineral density (vTBMD) measured at the distal end of the femur was significantly lower not only in both Orch groups but also in Sham + VOR. The decrease of cancellous bone density in Sham + VOR was lower than in the orchidectomized animals. A relative decrease of femoral inner and outer diameters compared with Sham and Base was observed in both Orch groups and in Sham + VOR, suggesting that both orchidectomy and VOR-treatment inhibited periosteal bone formation and endosteal bone resorption. Only orchidectomy, however, resulted in a decrease of cortical thickness. Bone area, mineral content, and density of both femora and lumbar vertebrae, measured by DXA, were decreased to a similar extent by VOR and Orch (bone mineral content of the femur was 467 +/- 18 mg in Orch and 461 +/- 10 mg in Sham +/- VOR vs. 521 +/- 11 mg in Sham; P < 0.001). In conclusion, treatment with the aromatase inhibitor VOR impairs body weight gain and skeletal modeling and decreases bone mineral density. Aromatase inhibition had similar final effects on bone mass and size as castration, but with less marked effects on bone turnover.
Assuntos
Inibidores da Aromatase , Densidade Óssea/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Triazóis/farmacologia , Absorciometria de Fóton , Envelhecimento , Animais , Peso Corporal , Fêmur , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Orquiectomia , Ratos , Ratos Wistar , Valores de ReferênciaRESUMO
Long-term diabetes in female rats preserves the bone mineral density (BMD) but impairs the strength of the femur. In this study, we have compared the effects of diabetes and high-dose 17 beta-estradiol (E2), two conditions of low bone formation, in ovariectomized (ovx) rats. Spontaneously diabetic BB rats were ovx 0-3 days after onset, and nondiabetic ovx littermates were used as controls; the rats were either untreated or treated with E2 (30 micrograms/day, subcutaneously), for 6 or 12 weeks (n = 9 in each of the eight groups). Analysis included: plasma 1,25-dihydroxyvitamin D3, insulin-like growth factor-I (IGF-I), and osteocalcin concentrations; histomorphometry of the proximal tibial metaphysis (PTM); and DXA and biomechanical testing of the femur. Both E2 treatment and diabetes markedly lowered plasma IGF-I and osteocalcin concentrations, as well as dynamic morphometric parameters of bone formation in the PTM. Plasma IGF-I and osteocalcin were correlated (R2 = 0.55; p < 0.0001). E2 treatment in both control and diabetic ovx rats increased the trabecular bone volume in the PTM and the BMD in the metaphysis of the distal femur; there was no difference between control and diabetic rats, however. The diaphyseal area and BMC were decreased in E2-treated or/and diabetic ovx rats, but the diaphyseal BMD remained unchanged compared with untreated ovx rats. The biomechanical properties of the whole femur (strength, angular deformation, and stiffness) were decreased in E2-treated and diabetic E2-treated ovx rats after 12 weeks. The data indicate that in situations of chronic low bone formation, whole bone strength does not reflect total BMD but correlates better with bone size and bone mineral content measurements.
Assuntos
Osso e Ossos/efeitos dos fármacos , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Estradiol/farmacologia , Animais , Fenômenos Biomecânicos , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Calcitriol/sangue , Cálcio/metabolismo , Diabetes Mellitus Tipo 1/fisiopatologia , Estradiol/administração & dosagem , Feminino , Fator de Crescimento Insulin-Like I/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Osteocalcina/sangue , Osteogênese/efeitos dos fármacos , Ovariectomia , Ovário/fisiologia , Ratos , Ratos Endogâmicos BB , Fatores de TempoRESUMO
This study aimed to evaluate whether recombinant human growth hormone (rhGH) or insulin-like growth factor-I (rhIGF-I) can reverse or prevent further bone loss in aged osteopenic ovariectomized (OVX) rats and to compare their effects with those of 17 beta-estradiol (E2). Twelve-month-old rats were OVX, remained untreated for 8 weeks, and subsequently received daily subcutaneous (SC) injections of rhGH (75 micrograms/day), rhIGF-I (250 micrograms/day), E2 (1.5 micrograms/day), and their respective combinations during 8 weeks, and were then compared with sham-operated, pretreatment OVX, and saline-treated OVX rats. A single sc injection of rhGH resulted in peak hGH concentrations after 90 minutes, with a half-life of 124 minutes; the highest plasma IGF-I concentrations were reached 45 minutes after rhIGF-I injection (+57% vs. baseline) with a gradual decline thereafter. Measurements included: biochemical parameters of bone remodeling (plasma osteocalcin and urinary pyridinolines); histomorphometry of proximal tibial metaphysis; DXA of femur; biomechanical analysis of femur and fifth lumbar vertebra (L5); plasma 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), and calbindin-D9K in duodenal mucosa. Whereas all E2-treated OVX rats had much suppressed bone remodeling, rhGH or rhIGF-I had no effect on any biochemical or histomorphometrical parameter of remodeling. The bone mineral density (BMD) at the distal femoral metaphysis as well as parameters of strength at L5 were maintained at pretreatment values in OVX rats treated with E2, GH, or IGF-I, but not in saline-treated OVX rats; their effects were not additive, however. Trabecular bone volume in the tibial metaphysis was also higher in rats treated with these agents than in saline-treated rats, but this was more apparent at the primary than at the secondary spongiosa, suggesting that their mechanism of action is on primary spongiosa formation or breakdown. E2 alone was ineffective to augment the BMD at the femoral diaphysis; however, the diaphyseal BMD was 12-14% higher (p < 0.01) after 8 weeks of GH treatment than in pretreatment or saline-treated OVX rats and sham-operated rats, while IGF-I was less effective than GH, GH or IGF-I treatment had no effect on plasma 1,25(OH)2D3 or duodenal calbindin-D9K concentrations, but the combination of GH or IGF-I with E2 potentiated the effect of E2 to stimulate calbindin-D9K concentrations and urinary calcium excretion, indicating "hyperabsorption hypercalciuria." In conclusion, the administration of rhGH and rhIGF-I, like that of E2, into aged OVX rats prevents further loss of bone mass and strength at sites containing trabecular bone. In addition, rhGH increases cortical bone mass above pretreatment values.
Assuntos
Osso e Ossos/efeitos dos fármacos , Estradiol/farmacologia , Hormônio do Crescimento Humano/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Minerais/metabolismo , Ovário/fisiologia , Absorciometria de Fóton , Envelhecimento/metabolismo , Animais , Quimioterapia Combinada , Feminino , Homeostase/efeitos dos fármacos , Humanos , Osteoporose/prevenção & controle , Ovariectomia , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologiaRESUMO
A nonsteroidal aromatase inhibitor vorozole (VOR) was administered to aged (12 months old) male Wistar rats and its effect was compared with the effect of androgen deficiency. The rats were either sham-operated (SHAM) or orchidectomized (ORCH) and treated with or without VOR. Thus, four experimental groups were created (SHAM, ORCH, SHAM + VOR, ORCH + VOR). The follow-up period was 4 months. At the end of the experimental period, bone mineral density (BMD) of the first four lumbar vertebrae and right femur was measured ex vivo with dual-energy X-ray absorptiometry, bone formation was evaluated by serum osteocalcin, and bone resorption by urinary excretion of (deoxy)pyridinoline. Orchidectomy increased bone resorption 2- to 3-fold whereas bone formation was only slightly increased. Treatment of intact male rats with VOR also increased bone resorption (+30% increase) whereas bone formation was not increased in this SHAM + VOR group. Their BMD was 7% lower in the femur (P < 0.01) and 6% lower in the lumbar vertebrae (P < 0.01) compared with the SHAM group that had not received VOR. Moreover, this decrease of bone mineral density was not significantly different from the expected decrease of bone density observed in the ORCH groups (6-10%). This was also reflected by a decrease of calcium content of the first four lumbar vertebrae of 15% (P < 0.001) in the SHAM + VOR group and 9-14% (P < 0.05) in the ORCH groups compared with the SHAM group, respectively. These data therefore suggest that inhibition of aromatization of androgens into estrogens increases bone resorption and bone loss similar to that observed after complete removal of androgens. Aromatization of androgens into estrogens may therefore, at least partly, explain the effects of androgens on skeletal maintenance.
Assuntos
Inibidores da Aromatase , Densidade Óssea/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Osteoporose/fisiopatologia , Triazóis/farmacologia , Absorciometria de Fóton , Envelhecimento/metabolismo , Envelhecimento/patologia , Aminoácidos/urina , Análise de Variância , Androgênios/química , Androgênios/metabolismo , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/urina , Cálcio/análise , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Estrogênios/química , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Vértebras Lombares/química , Vértebras Lombares/efeitos dos fármacos , Vértebras Lombares/fisiologia , Masculino , Orquiectomia , Osteocalcina/sangue , Ratos , Ratos Wistar , Triazóis/administração & dosagem , Triazóis/uso terapêuticoRESUMO
We studied the effects of recombinant human IGF-I (250 micrograms/day) and/or 17 beta-oestradiol (E2; 5 or 50 micrograms/kg/day), s.c., for 28 days, on plasma IGF-I and 1,25-(OH)2 vitamin D3 concentrations and on biochemical indices of bone remodelling (plasma osteocalcin, urinary pyridinolines) in 3 month-old rats that had been ovariectomised (OVX) 6 weeks before. Ten weeks after ovariectomy, plasma 1,25-(OH)2D3 was increased, but IGF-I and bone remodelling indices were within the normal range. RhIGF-I administration to OVX rats increased both IGF-I and 1,25-(OH)2D3 concentrations, as well as plasma osteocalcin and urinary pyridinoline excretion. By contrast, E2 decreased plasma IGF-I and 1,25-(OH)2D3 and the markers of bone remodelling. The combination of rhIGF-I and E2 resulted in intermediate effects. Multiple regression analysis showed that IGF-I correlated with plasma osteocalcin, and also with the urinary excretion of pyridinolines. The data shows that rhIGF-I stimulates bone remodelling in growing OVX rats, and that circulating IGF-I is a determinant of bone remodelling in vivo.
Assuntos
Remodelação Óssea/fisiologia , Estradiol/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Ovariectomia , Aminoácidos/urina , Animais , Biomarcadores/sangue , Biomarcadores/urina , Glicemia/metabolismo , Remodelação Óssea/efeitos dos fármacos , Calcitriol/sangue , Interações Medicamentosas , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Osteocalcina/sangue , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologia , Valores de ReferênciaRESUMO
Maternal and fetal 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and osteocalcin were measured in guinea pigs, to examine their potential use as animal models for fetal bone development and calcium homeostasis. Measurements were performed on days 42, 57 and 63 of gestation. Maternal serum total 1,25(OH)2D3 concentrations were increased only at the end of gestation (day 63). However, because the vitamin D binding protein (DBP) and albumin levels were decreased by 35-50% from day 42 onwards, the unbound 1,25(OH)2D3, calculated as the 1,25(OH)2D3/DBP molar ratio, was increased before day 63. Osteocalcin concentrations during gestation were 50-54% of levels found in nongravid animals. Fetal serum total 1,25(OH)2D3 concentrations were 20% of those in maternal guinea pigs. Since DBP levels were only 9-15% of maternal levels, the unbound 1,25(OH)2D3 was consistently higher in fetuses, from day 42 onwards. There was a rise in total and unbound 1,25(OH)2D3 between days 57 and 63 of fetal life. Osteocalcin concentrations were higher in fetal than in adult guinea pigs, and reached peak values on day 57 (1023 micrograms/l, i.e. 4.2 times higher than in adult female guinea pigs). Fetuses of guinea pigs that had received a restricted food supply for 14 days (days 49-63) had normal 1,25(OH)2D3 concentrations, but decreased osteocalcin concentrations compared with normal fetuses. The data obtained in fetal guinea pigs are comparable with those found in human fetuses, and suggest that the guinea pig may be a suitable model for studies on fetal bone and mineral development.
Assuntos
Calcitriol/sangue , Sangue Fetal/metabolismo , Osteocalcina/sangue , Prenhez/sangue , Animais , Osso e Ossos/embriologia , Cálcio/sangue , Feminino , Cobaias , Fosfatos/sangue , Gravidez , Albumina Sérica/metabolismo , Proteína de Ligação a Vitamina D/sangueRESUMO
Bone loss during androgen deficiency has been associated with accelerated bone turnover and imbalance between bone formation and resorption but the relative increase of both phenomena is not well described. Serum osteocalcin as marker of bone formation and urinary excretion of pyridinoline (PYD) and deoxypyridinoline (DPD) as markers of bone resorption were measured in both orchidectomized (ORCH, n = 8) and sham-operated (SHAM, n = 8) aged (12-month-old) male rats from 2 days before until 66 days after surgery. PYD and DPD were significantly higher in the ORCH group compared to the SHAM group starting from 21 days after surgery until the end of the experiment. Serum osteocalcin was only significantly increased in the ORCH group at 30 and 40 days. The maximal increase of serum osteocalcin was also smaller than the increase in PYD and DPD (30% versus 74% and 112%, respectively). The two markers of bone resorption were correlated with osteocalcin (r = 0.63 for PYD and r = 0.71 for DPD). Based on these results, we conclude that (1) bone resorption, as measured by PYD and DPD, increased during androgen deficiency; (2) moreover, the increase of bone resorption, as measured by DPD and PYD, was followed by a more moderate increase in bone formation as measured by serum osteocalcin, supporting the hypothesis that androgen deficiency causes accelerated bone turnover and imbalance between bone resorption and bone formation.
Assuntos
Aminoácidos/urina , Androgênios/deficiência , Desenvolvimento Ósseo/fisiologia , Reabsorção Óssea/urina , Osteocalcina/sangue , Análise de Variância , Animais , Biomarcadores , Peso Corporal , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Masculino , Osteoporose/sangue , Osteoporose/fisiopatologia , Osteoporose/urina , Ratos , Ratos Wistar , Padrões de ReferênciaRESUMO
Androgens have important effects on bone in vivo, possibly by direct activation of the androgen receptors in osteoblasts. To test this hypothesis, calcium homeostasis, bone mass, and bone turnover were evaluated in mature (4-month-old) androgen-resistant (testicular feminized, TFM) male rats. Data were compared with data from both female and male littermates of the same age and strain. Compared to normal males, TFM had similar serum testosterone, twofold higher estradiol and estrone, and sixfold higher androstenedione concentrations. Compared to normal females, TFM rats showed lower estradiol but also elevated concentrations of androstenedione and estrone. Despite similar free 1,25-(OH)2D3 concentrations, both TFM and male rats maintained higher serum calcium and phosphate concentrations than their female littermates. Serum IGF-I concentrations in TFM rats were decreased compared to male rats (-12%) or female rats (-27%). Serum osteocalcin concentrations, however, were twofold higher in TFM rats than in females but not significantly different from males. Femoral length, diameter, and cortical thickness were intermediate between those of males and females. The cancellous bone density of the femur and cancellous bone volume of the proximal metaphysis of the tibia, however, were not significantly different between groups. The ash weight of the tibia was also not significantly different, and the ash weight of the four distal lumbar vertebrae ranged between male and female values. Bone mechanical properties as measured by torsional strength and energy absorption of the femur were lower in TFM than in females but not different from males.(ABSTRACT TRUNCATED AT 250 WORDS)