| 1. |
- Boguszewski, M. C. S., et al.
(författare)
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Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement
- 2022
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 186:6
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Tidskriftsartikel (refereegranskat)abstract
- Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.
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| 2. |
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| 3. |
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| 4. |
- Munns, CF, et al.
(författare)
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Global Consensus Recommendations on Prevention and Management of Nutritional Rickets
- 2016
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Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 85:2, s. 83-106
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication. <b><i>Evidence:</i></b> A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describes the strength of the recommendation and the quality of supporting evidence. <b><i>Process:</i></b> Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus. <b><i>Results:</i></b> This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts. <b><i>Conclusion:</i></b> Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.
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| 5. |
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| 6. |
- Newton, P. T., et al.
(författare)
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A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 567:7747
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Tidskriftsartikel (refereegranskat)abstract
- Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification(1). However, it remains unknown how this supply is maintained throughout childhood growth. Chondroprogenitors in the resting zone are thought to be gradually consumed as they supply cells for longitudinal growth(1,2), but this model has never been proved. Here, using clonal genetic tracing with multicolour reporters and functional perturbations, we demonstrate that longitudinal growth during the fetal and neonatal periods involves depletion of chondroprogenitors, whereas later in life, coinciding with the formation of the secondary ossification centre, chondroprogenitors acquire the capacity for self-renewal, resulting in the formation of large, stable monoclonal columns of chondrocytes. Simultaneously, chondroprogenitors begin to express stem cell markers and undergo symmetric cell division. Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signalling pathways. Our findings indicate that a stem cell niche develops postnatally in the epiphyseal growth plate, which provides a continuous supply of chondrocytes over a prolonged period.
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| 7. |
- Allen, D. B., et al.
(författare)
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GH safety workshop position paper: a critical appraisal of recombinant human GH therapy in children and adults
- 2016
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 174:2
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Tidskriftsartikel (refereegranskat)abstract
- Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that 'for approved indications, GH is safe'; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.
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| 8. |
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Velentza, L., et al.
(författare)
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Pharmacological inhibition of BCL-2 with the FDA-approved drug venetoclax impairs longitudinal bone growth
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Treatment-related skeletal complications are common in childhood cancer patients and survivors. Venetoclax is a BCL-2 inhibitor that has shown efficacy in hematological malignancies in adults and is being investigated in pediatric cancer clinical trials as a promising therapeutic modality. Venetoclax triggers cell death in cancer cells, but whether it exerts similar effects in normal bone cells, is unknown. Chondrogenic ATDC5 cells, E20 fetal rat metatarsal bones, and human growth plate biopsies were treated with different concentrations of venetoclax. Female NMRI nu/nu mice were treated with venetoclax or vehicle for 15 days. Mice were X-rayed at baseline and at the end of the experiment to assess longitudinal bone growth and body weight was monitored throughout the study. Histomorphometric and immunohistochemical analyses were performed to evaluate treatment effects on the growth plate cartilage. Venetoclax decreased the viability of chondrocytes and impaired the growth of ex vivo cultured metatarsals while reducing the height of the resting/proliferative zone and the hypertrophic cell size. When tested in vivo, venetoclax suppressed bone growth and reduced growth plate height. Our experimental data suggest that venetoclax directly targets growth plate chondrocytes suppressing bone growth and we, therefore, encourage careful monitoring of longitudinal bone growth if treating growing children with venetoclax.
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| 15. |
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| 16. |
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| 17. |
- Ahmed, SF, et al.
(författare)
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Promoting growth in chronic inflammatory disease: lessons from studies of the growth plate
- 2009
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Ingår i: Hormone research. - : S. Karger AG. - 1423-0046. ; 7272 Suppl 1, s. 42-47
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Growth disorders are commonly observed in children with chronic inflammatory disease. It is likely that these disorders are mediated by a combination of factors, including the disease process and its treatment (with drugs such as glucocorticoids [GCs]). These factors affect the growth hormone-insulin-like growth factor I (IGF-I) axis, which is crucial for promoting linear growth at the level of the growth plate. Recent advances in our knowledge of the effects of GCs and proinflammatory cytokines on the growth plate have led to an improved understanding of the biological rationale for the use of growth-promoting therapy in children with chronic inflammatory disease and concurrent growth retardation. <i>Conclusions:</i> Both GCs and proinflammatory cytokines can adversely affect a number of components of growth plate chondrogenesis, and these effects can be ameliorated by raising local IGF-I exposure. However, this intervention does not lead to complete normalization of the growth plate. In children with chronic inflammation, the cornerstone of improving growth remains the judicious use of GCs while ensuring effective control of the disease process.
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| 18. |
- Andrade, AC, et al.
(författare)
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Hormones and genes of importance in bone physiology and their influence on bone mineralization and growth in Turner syndrome
- 2010
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Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 73:3, s. 161-165
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Tidskriftsartikel (refereegranskat)abstract
- This mini review summarizes papers presented in a Joint Symposium between the Bone, Growth Plate and Turner Syndrome Working Groups of the European Society for Paediatric Endocrinology (ESPE) that was held on September 9, 2009, in New York.The program had been composed to give an update on hormones and genes of importance in bone physiology and their influence on bone mineralization and growth in Turner syndrome. This paper summarizes the data and highlights the main topics and discussions related to each presentation.
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| 19. |
- Baron, J, et al.
(författare)
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Short and tall stature: a new paradigm emerges
- 2015
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Ingår i: Nature reviews. Endocrinology. - : Springer Science and Business Media LLC. - 1759-5037 .- 1759-5029. ; 11:12, s. 735-746
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Tidskriftsartikel (refereegranskat)
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| 20. |
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| 21. |
- Benjamin, RW, et al.
(författare)
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Hypercalcemia in children
- 2008
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Ingår i: Pediatric endocrinology reviews : PER. - 1565-4753. ; 5:3, s. 778-84
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Tidskriftsartikel (refereegranskat)
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| 22. |
- Benyi, E., et al.
(författare)
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Risks of Malignant and Non-Malignant Tumours in Tall Women Treated with High-Dose Oestrogen during Adolescence
- 2014
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Ingår i: Hormone Research in Paediatrics. - : S. Karger AG. - 1663-2818 .- 1663-2826. ; 82:2, s. 89-96
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: High-dose oestrogen treatment has been used to reduce growth in tall adolescent girls. The long-term safety with regard to cancer has not been clarified. Our aim was to study if this growth reduction therapy affects cancer risk later in life. Methods: A cohort study of 369 (172 treated, 197 untreated) Swedish women who in 1973-1993 were assessed for tall adolescent stature was designed. Data were collected from university hospital records, patient questionnaires, and the Swedish Cancer Register. Results: Risks are presented as odds ratios (ORs) with 95% confidence intervals comparing treated to untreated subjects. In treated subjects, the overall OR for having a tumour (malignant or nonmalignant) was 1.7 (0.8-3.8). The ORs were 2.3 (0.4-12.8) for breast tumours, 0.8 (0.2-2.6) for gynaecological tumours, and 6.1 (1.04-infinity) for melanoma. When limiting to malignant tumours, the crude ORs were of similar magnitude. Conclusion: The OR for any melanoma was higher in treated than in untreated women, suggesting an increased risk of melanoma associated with high-dose oestrogen treatment during adolescence. Although the risk estimates were increased for overall tumours, breast tumours, malignant gynaecological tumours, and malignant melanoma, these associations were not statistically significant. Our results need to be verified in a larger cohort.
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| 23. |
- Benyi, E, et al.
(författare)
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The Physiology of Childhood Growth: Hormonal Regulation
- 2017
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Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 88:1, s. 6-14
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Tidskriftsartikel (refereegranskat)abstract
- The growth patterns of a child changes from uterine life until the end of puberty. Height velocity is highest in utero and declines after birth until puberty when it rises again. Important hormonal regulators of childhood growth are growth hormone, insulin-like growth factor 1, sex steroids, and thyroid hormone. This review gives an overview of these hormonal regulators of growth and their interplay with nutrition and other key players such as inflammatory cytokines.
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| 24. |
- Bergstrom, I, et al.
(författare)
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Vitamin D levels in children born to vitamin D-deficient mothers
- 2013
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Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 80:1, s. 6-10
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Aim:</i></b> To determine whether a standard daily dose of 400 IU vitamin D is sufficient to normalize vitamin D levels in infants born to vitamin D-deficient mothers. <b><i>Methods:</i></b> The children were recruited from a study cohort of 68 immigrant and 51 non-immigrant pregnant women living in Stockholm. The women were monitored at 12 weeks of pregnancy, at delivery and together with their children, 6-18 months after birth. During pregnancy, most immigrant women (78%) had 25(OH)D<sub>3</sub> levels <25 nmol/l. We here report the outcome of 25 infants born to these mothers. All infants received a daily supplementation dose of 400 IU vitamin D from 2 weeks of age. <b><i>Results:</i></b> At birth, most children in the immigrant group were vitamin D-deficient (23.3 nmol/l (12-54); mean and range) while at 6-18 months of age vitamin D levels were essentially normalized (82.8 nmol/l (38-142)) although 4 children still had subnormal levels consistent with vitamin D insufficiency. <b><i>Conclusion:</i></b> A daily recommended supplementation dose of 400 IU vitamin D is sufficient in most children of vitamin D-deficient immigrant women living in Sweden.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Borjesson, AE, et al.
(författare)
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The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice
- 2012
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 302:11, s. E1381-E1389
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Tidskriftsartikel (refereegranskat)abstract
- High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα−/−) or ERαAF-1 (ERαAF-10) were evaluated. Old (16- to 19-mo-old) female ERα−/−mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-10mice (tibia: −4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-10mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα−/−mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.
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| 29. |
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| 30. |
- Börjesson, Anna E, et al.
(författare)
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The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice
- 2012
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 302:11
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Tidskriftsartikel (refereegranskat)abstract
- Borjesson AE, Windahl SH, Karimian E, Eriksson EE, Lagerquist MK, Engdahl C, Antal MC, Krust A, Chambon P, Savendahl L, Ohlsson C. The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice. Am J Physiol Endocrinol Metab 302: E1381-E1389, 2012. First published March 13, 2012; doi:10.1152/ajpendo.00646.2011.-High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-alpha stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ER alpha and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ER alpha (ER alpha(-/-)) or ER alpha AF-1 (ER alpha AF-1(0)) were evaluated. Old (16- to 19-mo-old) female ER alpha(-/-) mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ER alpha AF-1(0) mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ER alpha AF-1(0) mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ER alpha(-/-) mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ER alpha or aromatase. In contrast, ER alpha AF-1 deletion results in a hyperactive ER alpha, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ER alpha that do not require AF-1 and that ER alpha AF-1 opposes growth plate closure.
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| 31. |
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| 32. |
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| 33. |
- Chagin, AS, et al.
(författare)
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Androgen receptor modulation does not affect longitudinal growth of cultured fetal rat metatarsal bones
- 2009
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Ingår i: Hormone research. - : S. Karger AG. - 1423-0046. ; 71:4, s. 219-227
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Systemic administration of the nonaromatizable androgen oxandrolone stimulates growth in girls with Turner syndrome and boys with a constitutional delay of growth and puberty. It is unknown if oxandrolone acts locally at the growth plate level to stimulate longitudinal bone growth. <i>Methods:</i> Metatarsal bones from female and male rat fetuses (day E20) were cultured for 14 days in the presence of oxandrolone, testosterone or the androgen receptor (AR) antagonist flutamide with/without insulin-like growth-factor-I (IGF-I) or charcoal-treated serum. <i>Results:</i> The AR was found to be expressed in both male and female fetal rat metatarsal bones. Neither oxandrolone nor testosterone had any effect on metatarsal bone growth when tested at a wide concentration range (1 n<i>M</i> to 10 μ<i>M</i>), not even in the presence of IGF-I (100 ng/ml) or charcoal-treated serum (10%). Bone growth was also unaffected when the AR was blocked by flutamide. Control experiments confirmed that metatarsal bone growth was significantly stimulated by IGF-I (p < 0.001). <i>Conclusion:</i> Modulation of AR activity in the fetal rat growth plate does not affect linear bone growth. Extrapolating from these in vitro data, it could be speculated that oxandrolone stimulates longitudinal bone growth in treated children by acting indirectly rather than directly through AR activation in growth plate chondrocytes.
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| 34. |
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| 35. |
- Chagin, AS, et al.
(författare)
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Genes of importance in the hormonal regulation of growth plate cartilage
- 2009
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Ingår i: Hormone research. - : S. Karger AG. - 1423-0046. ; 7171 Suppl 2, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- Longitudinal bone growth occurs in the growth plate through a process in which resting zone chondrocytes are recruited to start active proliferation and then undergo differentiation, followed by apoptosis and later mineralization. Bone growth is controlled by a multitude of genes encoding for hormones and growth factors acting systemically and/or locally in the growth plate. From studies of individuals with a mutated aromatase gene and a male patient with defective oestrogen receptor (ER) α, it has become clear that the action of oestrogen is indispensable for normal pubertal growth and growth plate fusion. As new aromatase inhibitors and specific modulators of ERs are developed, these could offer more specific ways to modulate longitudinal growth and growth plate fusion. It is difficult to extrapolate data obtained in experimental animals, as clear species differences exist, emphasizing the need for new models that will allow studies in human growth plate cartilage.
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| 36. |
- Chagin, AS, et al.
(författare)
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Locally produced estrogen promotes fetal rat metatarsal bone growth; an effect mediated through increased chondrocyte proliferation and decreased apoptosis
- 2006
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Ingår i: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 188:2, s. 193-203
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Tidskriftsartikel (refereegranskat)abstract
- The importance of estrogens for the regulation of longitudinal bone growth is unequivocal. However, any local effect of estrogens in growth plate cartilage has been debated. Recently, several enzymes essential for estrogen synthesis were shown to be expressed in rat growth plate chondrocytes. Local production of 17β-estradiol (E2) has also been demonstrated in rat costal chondrocytes. We aimed to determine the functional role of locally produced estrogen in growth plate cartilage. The human chondrocyte-like cell line HCS-2/8 was used to study estrogen effects on cell proliferation (3H-labeled thymidine uptake) and apoptosis (cell death detection ELISA kit). Chondrocyte production of E2 was measured by RIA and organ cultures of fetal rat metatarsal bones were used to study the effects of estrogen on longitudinal growth rate. We found that significant amounts of E2 were produced by HCS-2/8 chondrocytes (64.1 ± 5.3 fmol/3 days/106cells). The aromatase inhibitor letrozole (1 μM) and the pure estrogen receptor antagonist ICI 182,780 (10 μM) inhibited proliferation of HCS-2/8 chondrocytes by 20% (P<0.01) and almost 50% (P<0.001), respectively. Treatment with ICI 182,780 (10 μM) increased apoptosis by 228% (P<0.05). Co-treatment with either caspase-3 or pan-caspase inhibitors completely blocked ICI 182,780-induced apoptosis (P<0.001 vs ICI 182,780 only). Moreover, both ICI 182,780 (10 μM) and letrozole (1 μM) decreased longitudinal growth of fetal rat metatarsal bones after 7 days of culture (P<0.01). In conclusion, our data clearly show that chondrocytes endogenously produce E2 and that locally produced estrogen stimulates chondrocyte proliferation and protects from spontaneous apoptosis. In addition, longitudinal growth is promoted by estrogens locally produced within the epiphyseal growth plate.
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| 37. |
- Chagin, AS, et al.
(författare)
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Oestrogen receptors and linear bone growth
- 2007
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Ingår i: Acta paediatrica (Oslo, Norway : 1992). - : Wiley. - 0803-5253 .- 1651-2227. ; 96:9, s. 1275-1279
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Tidskriftsartikel (refereegranskat)
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Chrysis, D, et al.
(författare)
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Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspases and suppression of the Akt-phosphatidylinositol 3'-kinase signaling pathway
- 2005
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:3, s. 1391-1397
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Tidskriftsartikel (refereegranskat)abstract
- Although glucocorticoids are known to induce apoptosis in chondrocytes, the mechanisms for this effect and the potential antiapoptotic role of IGF-I are unknown. To address this, we studied the effects of dexamethasone (Dexa) on apoptosis in the HCS-2/8 chondrocytic cell line. Dexa (25 μm) increased apoptosis (cell death ELISA) by 39% and 45% after 48 and 72 h, respectively (P < 0.01 and P < 0.05, respectively). IGF-I (100 ng/ml) decreased Dexa-induced apoptosis to levels similar to control cells. Apoptosis was associated with cleavage of poly-ADP-ribose polymerase (PARP) and α-fodrin and activation of caspases-8, -9, and -3 (Western), an effect that was counteracted when chondrocytes were cocultured with Dexa + IGF-I. Inhibitors for caspases-8, -9, and -3 (50 μm each) equally suppressed Dexa-induced apoptosis (P < 0.01). Time-response experiments showed that caspase-8 was activated earlier (at 12 h) than caspase-9 (at 36 h). We studied the phosphatidylinositol 3′-kinase (PI3K) pathway to further investigate the mechanisms of Dexa-induced apoptosis. Dexa decreased Akt phosphorylation by 93% (P < 0.001) without affecting total Akt and increased the p85α subunit 4-fold. The Akt inhibitor SH-6 (10 μm) increased apoptosis by 54% (P < 0.001). When combining Dexa with SH-6, apoptosis was not further increased, showing that Dexa-induced apoptosis is mediated through inhibition of the PI3K pathway. Addition of IGF-I to SH-6- or Dexa + SH-6-treated cells decreased apoptosis by 21.2% (P < 0.001) and 20.6% (P < 0.001), respectively. We conclude that Dexa-induced apoptosis is caspase dependent with an early activation of caspase-8. IGF-I can rescue chondrocytes from Dexa-induced apoptosis partially through the activation of other pathways than the PI3K signaling pathway. Based on our in vitro data, we speculate that in vivo treatment with glucocorticoids may diminish longitudinal growth by increasing apoptosis of proliferative growth plate chondrocytes.
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| 42. |
- Chrysis, D, et al.
(författare)
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Growth retardation induced by dexamethasone is associated with increased apoptosis of the growth plate chondrocytes
- 2003
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Ingår i: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 176:3, s. 331-337
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Tidskriftsartikel (refereegranskat)abstract
- Glucocorticoids cause significant growth retardation in mammals and humans and decreased proliferation of chondrocytes has been considered as the main local mechanism. Death by apoptosis is an important regulator of homeostasis in multicellular organisms. Here we chose to study the role of apoptosis in growth retardation caused by glucocorticoid treatment. We treated 7-week-old male rats with dexamethasone (5 mg/kg/day) for 7 days. Apoptosis was studied in tibiae growth plates by the TUNEL method. Immunoreactivity for parathyroid hormone-related peptide (PTHrP), caspase-3, and the anti-apoptotic proteins Bcl-2 and Bcl-x was also studied. Apoptosis was mainly localized in terminal hypertropic chondrocytes (THCs) in both control and dexamethasone-treated animals. Dexamethasone caused an increase in apoptosis which was fourfold in THCs (2.45+/-0.12 vs 0.62+/-0.09 apoptotic cells/mm growth plate, P<0.001), and 18-fold in proliferative chondrocytes (0.18+/-0.04 vs 0.01+/-0.007 apoptotic cells/mm growth plate, P<0.001). Increased apoptosis after dexamethasone treatment was accompanied by increased immunoreactivity for caspase-3 and decreased immunoreactivity for the anti-apoptotic proteins Bcl-2 and Bcl-x, which further supports our apoptosis results. Dexamethasone also decreased the immunoreactivity for PTHrP, suggesting a role in the mechanism by which glucocorticoids induce apoptosis in the growth plate. We conclude that apoptosis is one mechanism involved in growth retardation induced by glucocorticoids. Premature loss of resting/proliferative chondrocytes by apoptosis could contribute to incomplete catch-up seen after prolonged glucocorticoid treatment.
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| 43. |
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| 44. |
- Dahl, S., et al.
(författare)
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High prevalence of pituitary hormone deficiency in both unilateral and bilateral optic nerve hypoplasia
- 2019
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 108:9, s. 1677-1685
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Tidskriftsartikel (refereegranskat)abstract
- Aim This study examined the prevalence of neurological impairment and pituitary hormone deficiency (PHD) in patients with unilateral and bilateral optic nerve hypoplasia (ONH). Methods A population-based cross-sectional cohort study of 65 patients (51% female) with ONH was conducted in Stockholm. Of these were 35 bilateral and 30 unilateral. The patients were below 20 years of age, living in Stockholm in December 2009 and found through database searching. The median age at the analysis of the results in January 2018 was 16.1 years (range 8.1-27.5 years). Neurological assessments and blood sampling were conducted, neuroradiology was reviewed and growth curves were analysed. Diagnoses of PHDs were based on clinical and biochemical evidence of hormone deficiency. Results Neurological impairments were identified in 47% of the patients and impairments in gross and fine motor function were more prevalent in bilateral ONH (p < 0.001). In addition, 9% had cerebral palsy and 14% had epilepsy. The prevalence of PHD was 29 and 19% had multiple PHD. Conclusion Children with ONH had a high risk of neurological impairment, especially in bilateral disease. Both unilateral and bilateral ONH signified an increased prevalence of PHD and all these children should be endocrinologically followed up until completed puberty.
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- Davenport, ML, et al.
(författare)
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Growth failure in early life: an important manifestation of Turner syndrome
- 2002
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Ingår i: Hormone research. - : S. Karger AG. - 0301-0163. ; 57:5-6, s. 157-164
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Tidskriftsartikel (refereegranskat)abstract
- The goals of this study were to test the hypothesis that girls with Turner syndrome (TS) experience growth failure early in life and to establish model-based normative growth charts for 0- to 8-year-old American girls with TS. Full-term girls with TS who had 5 or more measurements of height obtained during their first 10 years of life prior to initiation of growth hormone, estrogen and/or androgen therapy were eligible for this study. A nonlinear mixed-effects model comprising the first two components of the infancy-childhood-puberty (ICP) model of growth was fitted to the longitudinal height measurements and compared with those of healthy American girls. Height measurements (n = 1,146) from 112 girls with TS (45,X: 57.1%; 45,X/46,XX: 12.5%; 46,X, iso(X): 4.5%, and other: 25.9%) were analyzed. Mean height SDS fell from –0.68 at birth to –1.60 at 1 year, –1.80 at 2 years and –1.95 at 3 years. When compared to controls (676 girls, 4,537 measurements), girls with TS grew more slowly due to three principal factors: a slow growth rate of the infancy component, a slow growth rate at the onset of the childhood component, and delayed onset of the childhood component. Traditional concepts of growth failure in TS should be revised. Physicians should consider the diagnosis of TS in any girl with unexplained failure to thrive or short stature, even in the first 3 years of life.
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| 47. |
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| 48. |
- Davenport, ML, et al.
(författare)
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Turner syndrome: a pattern of early growth failure
- 1999
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Ingår i: Acta paediatrica (Oslo, Norway : 1992). Supplement. - : Wiley. - 0803-5326 .- 0803-5253 .- 1651-2227. ; 88:433, s. 118-121
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Tidskriftsartikel (refereegranskat)
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