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- Chagin, AS, et al.
(author)
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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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In: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 188:2, s. 193-203
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Journal article (peer-reviewed)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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| 8. |
- Chrysis, D, et al.
(author)
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Growth retardation induced by dexamethasone is associated with increased apoptosis of the growth plate chondrocytes
- 2003
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In: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 176:3, s. 331-337
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Journal article (peer-reviewed)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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| 9. |
- Enberg, B, et al.
(author)
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Characterisation of novel missense mutations in the GH receptor gene causing severe growth retardation
- 2000
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In: European journal of endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 143:1, s. 71-76
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Journal article (peer-reviewed)abstract
- Two Swedish brothers, 2.5 and 4 years of age, were found to fulfil all the clinical and laboratory characteristics of Laron's syndrome. They were shown to have unique missense mutations in the GH receptor gene. Both of their parents were of normal height, but they both separately carried one of the identified gene alterations. A molecular model of the first receptor alteration suggests that a collapse in three-dimensional receptor structure most likely contributed to the GH insensitivity in these patients.
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- Hagenfeldt, K, et al.
(author)
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Bone mass and body composition of adult women with congenital virilizing 21-hydroxylase deficiency after glucocorticoid treatment since infancy
- 2000
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In: European journal of endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 143:5, s. 667-671
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Journal article (peer-reviewed)abstract
- AIM: To study bone mass, body composition and androgenic/anabolic activity in adult women with virilizing congenital adrenal hyperplasia (CAH) treated with glucocorticoids since infancy and to relate this to the postmenarcheal glucocorticoid impact. PATIENTS AND METHODS: Thirteen adult women with virilizing CAH treated with gluco- and mineralocorticoids but otherwise medicine-free were investigated with respect to bone mineral content, body composition by dual energy X-ray absorptiometry and endocrine status. In addition an index of accumulated postmenarcheal exogenous glucocorticoid impact was calculated. Seven of the patients had regular menstrual periods, and six were oligomenorrheic but responded with withdrawal bleedings on cyclic progestagens. The data for the patients were compared with those of age-matched healthy reference subjects. RESULTS: In spite of their shorter stature, CAH patients were significantly heavier and had a significantly higher body mass index and fat/lean body mass ratio than the controls. Their bone mineral area density (BMD) was significantly lower than that of the controls. Serum concentrations of androgens were subnormal in all except two of the patients. Strong negative associations were found between BMD and the calculated index of accumulated postmenarcheal glucocorticoid dose but not between BMD and circulating androgen levels. CONCLUSION: The results indicate that glucocorticoids were administered in excess in most of the patients, resulting in subnormal levels of adrenocortical androgens, increased body fat and bone demineralization. Increased catabolic activity due to hypercortisolism rather than decreased androgenic/anabolic steroids is probably the major cause of the subnormal BMD in the treated CAH patients.
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- Kollin, C, et al.
(author)
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Growth of spontaneously descended and surgically treated testes during early childhood
- 2013
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In: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 131:4, s. E1174-E1180
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Journal article (peer-reviewed)abstract
- To investigate whether in congenital unilateral cryptorchidism the growth of a spontaneously descended testis is normal, compared with the contralateral scrotal testis or similar to the growth of testes that failed to descend spontaneously and later underwent orchidopexy.METHODS:Ninety-one boys with congenital unilateral cryptorchidism with later spontaneous descent of the initially retained testis were followed from birth (0–3 weeks) up to 5 years of age and compared with boys randomized to surgery at either 9 months (n = 78) or 3 years (n = 85) of age. Testicular volume was determined with ultrasonography.RESULTS:Eighty-two percent of spontaneous descent occurred before 2 months of age. Twenty-two percent of these descended testes were later again found in a retained position. The spontaneously descended testis was smaller than its scrotal counterpart at all ages (P < .001). We also showed a significant difference in the testicular volume between the early and late treated boys from age 2 years and onward. At 2, 4, and 5 years of age, the volumes of the spontaneously descended testes were significantly larger than those of boys operated on at 3 years but similar to those operated on at 9 months.CONCLUSIONS:We have shown that in boys with congenital unilateral cryptorchidism with later spontaneous descent, the originally retained testes show impaired growth compared with its scrotal counterpart from birth and onwards. Also, they are prone to later ascent to a retained position. Furthermore, the longer testes remain untreated the more they exhibit impaired growth.
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| 26. |
- Lindgren, AC, et al.
(author)
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Growth hormone treatment of children with Prader-Willi syndrome: effects on glucose and insulin homeostasis. Swedish National Growth Hormone Advisory Group
- 1999
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In: Hormone research. - : S. Karger AG. - 0301-0163. ; 51:4, s. 157-161
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Journal article (peer-reviewed)abstract
- Insulin and glucose homeostasis have been studied during growth hormone (GH) treatment in 19 prepubertal children with Prader-Willi syndrome (PWS) and compared with 11 healthy prepubertal obese children. Before treatment, insulin levels in children with PWS were lower (p < 0.01) than in healthy obese children. During GH treatment, fasting insulin levels increased in children with PWS (p < 0.001). Glucose levels were similar for PWS and obese children before treatment. Children with PWS showed a slow glucose disappearance rate (k = 1.7%) which deteriorated (k = 1.3%, p < 0.001) during GH treatment. HbA1c and fasting glucose levels remained normal. Thus, GH treatment of children with PWS resulted in increased insulin blood levels, unchanged fasting glucose and HbA1c but decreased glucose elimination rate after an intravenous glucose test. However, the observed dose-dependent increase in insulin levels during GH treatment, that reached supranormal concentrations in 6/19 patients, and the occurrence of NIDDM in 1 patient during follow-up suggest that close surveillance and low doses of GH should be applied, especially if the PWS patient is very obese.
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| 27. |
- Muller, J, et al.
(author)
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Management of males with 45,X/46,XY gonadal dysgenesis
- 1999
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In: Hormone research. - : S. Karger AG. - 0301-0163. ; 52:1, s. 11-14
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Journal article (peer-reviewed)abstract
- Males with the 45,X/46,XY karyotype and malformations of the external genitalia carry an increased risk of developing germ cell neoplasia of the gonads. We have studied gonadal tissue from 10 individuals, 0.3–17 years of age, with a male phenotype and either hypospadias and/or cryptorchidism. Four patients, 0.3–15 years of age, had carcinoma in situ, 1 boy had Sertoli-cell-only pattern and the remainder prepubertal histology. Gonadoblastoma or invasive carcinoma was not found. On the basis of our current knowledge we propose a strategy for management and follow-up of these boys in order to detect possible premalignant histological changes early and prevent development of a gonadal tumour.
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| 28. |
- Nilsson, L O, et al.
(author)
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Demonstration of estrogen receptor-beta immunoreactivity in human growth plate cartilage.
- 1999
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X. ; 84:1, s. 370-3
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Journal article (peer-reviewed)abstract
- Estrogens affect longitudinal bone growth through their action on endochondral bone formation. Two estrogen receptors are known, the classical estrogen receptor-alpha (ER alpha), newly demonstrated in human growth plate cartilage, and a recently cloned estrogen receptor-beta (ER beta). The present study aimed to localize a possible expression of ER beta protein in human growth plates. Tissue samples were obtained from tibial and femoral growth plates in four female pubertal patients undergoing epiphyseal surgery. Immunohistochemistry, using two different ER beta-specific antibodies, demonstrated positive staining for ER beta in hypertrophic epiphyseal chondrocytes from all patients. No staining was noted in resting or proliferative chondrocytes. These data suggest that in addition to ER alpha, human epiphyseal chondrocytes also express ER beta. The physiological role of ER beta in the regulation of longitudinal bone growth in humans remains to be elucidated.
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| 29. |
- Nilsson, O, et al.
(author)
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Estrogen receptor-alpha and -beta are expressed throughout postnatal development in the rat and rabbit growth plate
- 2002
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In: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 173:3, s. 407-14
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Journal article (peer-reviewed)abstract
- Estrogen regulates skeletal growth and promotes epiphyseal fusion. To explore the mechanisms underlying these effects we investigated the expression of estrogen receptor-alpha (ERalpha) and -beta (ERbeta) in rat and rabbit growth plates during postnatal development, using immunohistochemistry. Immunoreactivity for ERalpha and ERbeta was observed in resting zone and proliferative zone chondrocytes at all ages studied for both rat (7, 14, 28 and 70 days of age) and rabbit (1, 7, 28 and 120 days of age). In the rat distal humerus and the rabbit proximal tibia, expression of both receptors in the hypertrophic zone was minimal at early ages, increasing only at the last time point prior to epiphyseal fusion. Expression was rarely seen in the hypertrophic zone of the rat proximal tibia, a growth plate that does not fuse until late in life. Therefore, we conclude that ERalpha and ERbeta are both expressed in the mammalian growth plate. The temporal and anatomical pattern suggests that ER expression in the hypertrophic zone in particular may play a role in epiphyseal fusion.
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| 30. |
- Nilsson, O, et al.
(author)
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Localization of estrogen receptors-alpha and -beta and androgen receptor in the human growth plate at different pubertal stages
- 2003
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In: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 177:2, s. 319-326
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Journal article (peer-reviewed)abstract
- Sex steroids are required for a normal pubertal growth spurt and fusion of the human epiphyseal growth plate. However, the localization of sex steroid receptors in the human pubertal growth plate remains controversial. We have investigated the expression of estrogen receptor (ER) alpha, ERbeta and androgen receptor (AR) in biopsies of proximal tibial growth plates obtained during epiphyseal surgery in 16 boys and eight girls. All pubertal stages were represented (Tanner stages 1-5). ERalpha, ERbeta and AR were visualized with immunohistochemistry and the number of receptor-positive cells was counted using an image analysis system. Percent receptor-positive chondrocytes were assessed in the resting, proliferative and hypertrophic zones and evaluated for sex differences and pubertal trends. Both ERalpha- and ERbeta-positive cells were detected at a greater frequency in the resting and proliferative zones than in the hypertrophic zone (64+/-2%, 64+/-2% compared with 38+/-3% for ERalpha, and 63+/-3%, 66+/-3% compared with 53+/-3% for ERbeta), whereas AR was more abundant in the resting (65+/-3%) and hypertrophic zones (58+/-3%) than in the proliferative zone (41+/-3%). No sex difference in the patterns of expression was detected. For ERalpha and AR, the percentage of receptor-positive cells was similar at all Tanner pubertal stages, whereas ERbeta showed a slight decrease in the proliferative zone during pubertal development (P<0.05). In summary, our findings suggest that ERalpha, ERbeta and AR are expressed in the human growth plate throughout pubertal development, with no difference between the sexes.
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| 31. |
- Nordenstrom, A, et al.
(author)
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Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11beta-hydroxysteroid dehydrogenase reductase activity
- 1999
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 84:4, s. 1210-1213
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Journal article (peer-reviewed)abstract
- Congenital adrenal hyperplasia in children is often treated with cortisone acetate and fludrocortisone. It is known that certain patients with congenital adrenal hyperplasia require very high substitution doses of cortisone acetate, and a few patients do not respond to this treatment at all.A patient with 21-hydroxylase deficiency, for whom elevated pregnanetriol (P3) levels in urine were not suppressed during treatment with cortisone acetate (65 mg/m2·day), was examined. The activation of cortisone to cortisol was assessed by measuring urinary metabolites of cortisone and cortisol.The patient’s inability to respond to treatment with cortisone acetate was found to be caused by a low conversion of cortisone to cortisol, assumed to be secondary to low 11β-hydroxysteroid dehydrogenase activity (11-oxoreductase deficiency). All exons and exon/intron junctions of the 11β-hydroxysteroid dehydrogenase type1 gene (HSD11L) were sequenced without finding any mutations, but a genetic lesion in the promoter or other regulatory regions cannot be ruled out. The deficient 11-oxoreductase activity seems to have been congenital, in this case, but can possibly be attributable to a down-regulation of the enzyme activity. The results support the use of hydrocortisone, rather than cortisone acetate, for substitution therapy in adrenal insufficiency.
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| 34. |
- Ritzen, EM
(author)
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Early puberty: what is normal and when is treatment indicated?
- 2003
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In: Hormone research. - : S. Karger AG. - 0301-0163. ; 6060 Suppl 3, s. 31-34
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Journal article (peer-reviewed)abstract
- Girls and boys who enter puberty before 8 and 9 years of age, respectively (corresponding to about –3 SDS), are arbitrarily considered to need referral for endocrine investigation. A recent report from the Lawson Wilkins Pediatric Endocrine Society suggested that the limit for investigation of girls and boys should be lowered to 7 and 8 years, respectively. For African-American girls, 6 years is the suggested age. This recommendation has been criticized. Although short stature is a common end result of precocious puberty, short- and long-term psychological symptoms may be more important, since several studies have indicated psychopathology in this patient group. Whether this can be prevented by gonadotropin releasing hormone agonist treatment remains to be shown. This review will highlight the psychological aspects of early puberty. In short, aspects other than height should also be evaluated when considering treatment of the early maturing child.
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| 35. |
- Ritzen, EM, et al.
(author)
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Estrogens and human growth
- 2000
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In: The Journal of steroid biochemistry and molecular biology. - 0960-0760. ; 74:5, s. 383-386
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Journal article (peer-reviewed)
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| 36. |
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| 37. |
- Ritzen, EM, et al.
(author)
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How can molecular biology contribute to the management of congenital adrenal hyperplasia?
- 2000
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In: Hormone research. - : S. Karger AG. - 0301-0163. ; 5353 Suppl 1, s. 34-37
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Journal article (peer-reviewed)abstract
- The most common form of congenital adrenal hyperplasia is due to a deficiency of 21-hydroxylase (21OHD) activity and is caused by a mutation in the CYP21 gene. By genotyping patients, new and important information can be gained, including presence or absence of 21OHD in borderline cases, determining the severity of disease and identifying heterozygote carriers. Current management of patients with 21OHD involves administering sufficient glucocorticoids to suppress excess adrenal androgen secretion, but not so much that bone growth and mineralization are impaired. New management strategies have been proposed and include administering only substitution doses of corticosteroids and counteracting side-effects by administering an anti-androgen and aromatase inhibitor. Adrenalectomy has also been proposed. Further investigation into these approaches is necessary.
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| 46. |
- Setchell, BP, et al.
(author)
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Reduction of long-term effects of local heating of the testis by treatment of rats with a GnRH agonist and an anti-androgen
- 2001
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In: Reproduction (Cambridge, England). - : Bioscientifica. - 1470-1626 .- 1741-7899. ; 122:2, s. 255-263
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Journal article (peer-reviewed)abstract
- Heating the testes of anaesthetized adult rats to 43 degrees C for 30 min in a waterbath was followed by a large decrease in testis and epididymis mass and number of spermatozoa 35 days later. These parameters had recovered to some extent, but not completely, by days 70 and 97 after heating, but had decreased again in rats examined on day 182. There were no consistent effects of heating on androgen status, as determined by the concentrations of testosterone in blood and testis fluids, or by seminal vesicle mass, and interstitial fluid volume was increased in the heated testes. Treatment of rats with an implant of a GnRH agonist and daily injections of an anti-androgen for 14 days (sufficient in itself to cause large temporary decreases in tissue mass, number of spermatozoa and androgen status) did not reduce the initial decrease in testis mass or number of spermatozoa seen after heating, but reduced the later decreases in mass and number of spermatozoa significantly. These findings indicate that, as well as causing damage to spermatocytes and spermatids, as previously reported, heating also reduces the ability of spermatogonia to repopulate the seminiferous tubules at longer intervals after heating. Furthermore, it appears that this effect on the spermatogonia can be reduced by treating the animals with a GnRH agonist and anti-androgen, a treatment similar to that shown by other authors to improve recovery of the testis from irradiation or drug treatment.
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