Twenty-four hours secretion pattern of serum estradiol in healthy prepubertal and pubertal boys as determined by a validated ultra-sensitive extraction RIA

<p>Abstract</p> <p>Background</p> <p>The role of estrogens in male physiology has become evident. However, clinically useful normative data for estradiol secretion in boys has not previously been established due to the insensitivity of current methods used in clinical routine. By use of a validated ultra-sensitive extraction RIA, our aim was to establish normative data from a group consisting of healthy boys in prepuberty and during pubertal development.</p> <p>Methods</p> <p>Sixty-two 24-hours serum profiles (6 samples/24 hours) were obtained from 44 healthy boys (ages; 7.2–18.6 years) during their pubertal development, classified into five stages: prepuberty (testis, 1–2 mL), early (testis, 3–6 mL), mid (testis, 8–12 mL), late-1 (testis,15–25 mL, not reached final height) and late-2 (testis,15–25 mL, reached final height). Serum estradiol was determined by an ultra- sensitive extraction radioimmunoassay with detection limit 4 pmol/L and functional sensitivity 6 pmol/L.</p> <p>Results</p> <p>Mean estradiol concentrations during 24-hours secretion increased from prepuberty (median: <4 (5–95 percentiles: <4 – 7) pmol/L) to early puberty (6 (<4 – 12 pmol/L) but then remained relatively constant until a marked increase between mid-puberty (8 (4 – 17) pmol/L) and late-1 (21 (12 – 37) pmol/L) puberty, followed by a slower increase until late-2 puberty (32 (20 – 47) pmol/L). The diurnal rhythm of serum estradiol was non-measurable in pre- and early puberty, but discerned in mid-puberty, and become evident in late pubertal stages with peak values at 0600 to 1000 h.</p> <p>Conclusion</p> <p>With the use of an ultra-sensitive extraction RIA, we have provided clinically useful normative data for estradiol secretion in boys.</p

Liver-Derived IGF-I Regulates Mean Life Span in Mice

Background: Transgenic mice with low levels of global insulin-like growth factor-I (IGF-I) throughout their life span, including pre- and postnatal development, have increased longevity. This study investigated whether specific deficiency of liver-derived, endocrine IGF-I is of importance for life span. Methods and Findings: Serum IGF-I was reduced by approximately 80 % in mice with adult, liver-specific IGF-I inactivation (LI-IGF-I-/- mice), and body weight decreased due to reduced body fat. The mean life span of LI-IGF-I-/- mice (n = 84) increased 10 % vs. control mice (n = 137) (Cox’s test, p,0.01), mainly due to increased life span (16%) of female mice [LI-IGF-I-/- mice (n = 31): 26.761.1 vs. control (n = 67): 23.060.7 months, p,0.001]. Male LI-IGF-I-/- mice showed only a tendency for increased longevity (p = 0.10). Energy expenditure, measured as oxygen consumption during and after submaximal exercise, was increased in the LI-IGF-I-/- mice. Moreover, microarray and RT-PCR analyses showed consistent regulation of three genes (heat shock protein 1A and 1B and connective tissue growth factor) in several body organs in the LI-IGF-I-/- mice. Conclusions: Adult inactivation of liver-derived, endocrine IGF-I resulted in moderately increased mean life span. Body weight and body fat decreased in LI-IGF-I-/- mice, possibly due to increased energy expenditure during exercise. Genes earlier reported to modulate stress response and collagen aging showed consistent regulation, providing mechanisms tha

Genetic Determinants of Serum Testosterone Concentrations in Men

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10−41 and rs6258, p = 2.3×10−22). Subjects with ≥3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10−16). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation

Reduced Bone Mass and Muscle Strength in Male 5α-Reductase Type 1 Inactivated Mice

Androgens are important regulators of bone mass but the relative importance of testosterone (T) versus dihydrotestosterone (DHT) for the activation of the androgen receptor (AR) in bone is unknown. 5α-reductase is responsible for the irreversible conversion of T to the more potent AR activator DHT. There are two well established isoenzymes of 5α-reductase (type 1 and type 2), encoded by separate genes (Srd5a1 and Srd5a2). 5α-reductase type 2 is predominantly expressed in male reproductive tissues whereas 5α-reductase type 1 is highly expressed in liver and moderately expressed in several other tissues including bone. The aim of the present study was to investigate the role of 5α-reductase type 1 for bone mass using Srd5a1−/− mice. Four-month-old male Srd5a1−/− mice had reduced trabecular bone mineral density (−36%, p<0.05) and cortical bone mineral content (−15%, p<0.05) but unchanged serum androgen levels compared with wild type (WT) mice. The cortical bone dimensions were reduced in the male Srd5a1−/− mice as a result of a reduced cortical periosteal circumference compared with WT mice. T treatment increased the cortical periosteal circumference (p<0.05) in orchidectomized WT mice but not in orchidectomized Srd5a1−/− mice. Male Srd5a1−/− mice demonstrated a reduced forelimb muscle grip strength compared with WT mice (p<0.05). Female Srd5a1−/− mice had slightly increased cortical bone mass associated with elevated circulating levels of androgens. In conclusion, 5α-reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength and we propose that these effects are due to lack of 5α-reductase type 1 expression in bone and muscle. In contrast, the increased cortical bone mass in female Srd5a1−/− mice, is an indirect effect mediated by elevated circulating androgen levels

Ablation of the Pro-Apoptotic Protein Bax Protects Mice from Glucocorticoid-Induced Bone Growth Impairment

Dexamethasone (Dexa) is a widely used glucocorticoid to treat inflammatory diseases; however, a multitude of undesired effects have been reported to arise from this treatment including osteoporosis, obesity, and in children decreased longitudinal bone growth. We and others have previously shown that glucocorticoids induce apoptosis in growth plate chondrocytes. Here, we hypothesized that Bax, a pro-apoptotic member of the Bcl-2 family, plays a key role in Dexa-induced chondrocyte apoptosis and bone growth impairment. Indeed, experiments in the human HCS-2/8 chondrocytic cell line demonstrated that silencing of Bax expression using small-interfering (si) RNA efficiently blocked Dexa-induced apoptosis. Furthermore, ablation of Bax in female mice protected against Dexa-induced bone growth impairment. Finally, Bax activation by Dexa was confirmed in human growth plate cartilage specimens cultured ex vivo. Our findings could therefore open the door for new therapeutic approaches to prevent glucocorticoid-induced bone growth impairment through specific targeting of Bax

Manual for DREAM version 3.2

The Driving Reliability and Error Analysis Method (DREAM) is based on the Cognitive Reliability and Error Analysis Method (CREAM; Hollnagel, 1998). CREAM was developed to analyse accidents within process control domains such as nuclear power plants and train operation, and DREAM is an adaptation of CREAM to suit the road traffic domain. The purpose of DREAM is to make it possible to systematically classify and store accident and incident causation information. This means that DREAM, like all other methods for accident/incident analysis, is not a provider but an organiser of explanations. For any of the contributing factor categories available in DREAM to be used, it must be supported by relevant empirical information. DREAM in itself cannot tell us why accidents happen (if it could, we would need neither on-scene investigations nor interviews).DREAM includes three main components: an accident model, a classification scheme and a detailed procedure description which step by step goes through what needs to be done in order to perform a DREAM analysis on an investigated accident/incident. Below, the accident model will be given more detailed descriptions. After this follows a description of the classification scheme, and then comes the analysis process, including example cases and recommendations for how to do the categorisation in certain typical scenarios

Manual for DREAM version 3.2

The Driving Reliability and Error Analysis Method (DREAM) is based on the Cognitive Reliability and Error Analysis Method (CREAM; Hollnagel, 1998). CREAM was developed to analyse accidents within process control domains such as nuclear power plants and train operation, and DREAM is an adaptation of CREAM to suit the road traffic domain. The purpose of DREAM is to make it possible to systematically classify and store accident and incident causation information. This means that DREAM, like all other methods for accident/incident analysis, is not a provider but an organiser of explanations. For any of the contributing factor categories available in DREAM to be used, it must be supported by relevant empirical information. DREAM in itself cannot tell us why accidents happen (if it could, we would need neither on-scene investigations nor interviews).DREAM includes three main components: an accident model, a classification scheme and a detailed procedure description which step by step goes through what needs to be done in order to perform a DREAM analysis on an investigated accident/incident. Below, the accident model will be given more detailed descriptions. After this follows a description of the classification scheme, and then comes the analysis process, including example cases and recommendations for how to do the categorisation in certain typical scenarios

Expression of vascular endothelial growth factor in the growth plate is stimulated by estradiol and increases during pubertal development

Longitudinal bone growth is regulated in the growth plate. At the end of puberty, growth velocity diminishes and eventually ceases with the fusion of the growth plate through mechanisms that are not yet completely understood. Vascular endothelial growth factor (VEGF) has an important role in angiogenesis, but also in chondrocyte differentiation, chondrocyte survival, and the final stages of endochondral ossification. Estrogens have been shown to up-regulate VEGF expression in the uterus and bone of rats. In this study, we investigated the relation between estrogens and VEGF production in growth plate chondrocytes both in vivo and in vitro. The expression of VEGF protein was down-regulated upon ovariectomy and was restored upon estradiol (E-2) supplementation in rat growth plates. In cultured rat chondrocyte cell line RCJ3.1C5.18, E-2 dose dependently stimulated 121 and 189 kDa isoforms of VEGF, but not the 164kDa isoform. Finally, VEGF expression was observed at both protein and mRNA levels in human growth plate specimens. The protein level increased during pubertal development, supporting a link between estrogens and local VEGF production in the growth plate. We conclude that estrogens regulate VEGF expression in the epiphyseal growth plate, although the precise role of VEGF in estrogen-mediated growth plate fusion remains to be clarified. Journal of Endocrinology (2010) 205, 61-68Bone and mineral researc