Sex steroids in relation to sexual and skeletal maturation in obese male adolescents.

BACKGROUND: Childhood obesity is associated with an accelerated skeletal maturation. However, data concerning pubertal development and sex steroid levels in obese adolescents are scarce and contrasting. OBJECTIVES: To study sex steroids in relation to sexual and skeletal maturation and to serum prostate specific antigen (PSA), as a marker of androgen activity, in obese boys from early to late adolescence. METHODS: Ninety obese boys (aged 10-19 y) at the start of a residential obesity treatment program and 90 age-matched controls were studied cross-sectionally. Pubertal status was assessed according to the Tanner method. Skeletal age was determined by an x-ray of the left hand. Morning concentrations of total testosterone (TT) and estradiol (E2) were measured by liquid chromatography-tandem mass spectrometry, free T (FT) was measured by equilibrium dialysis, and LH, FSH, SHBG, and PSA were measured by immunoassays. RESULTS: Genital staging was comparable between the obese and nonobese groups, whereas skeletal bone advancement (mean, 1 y) was present in early and midadolescence in the obese males. Although both median SHBG and TT concentrations were significantly (P < .001) lower in obese subjects during mid and late puberty, median FT, LH, FSH, and PSA levels were comparable to those of controls. In contrast, serum E2 concentrations were significantly (P < .001) higher in the obese group at all pubertal stages. CONCLUSION: Obese boys have lower circulating SHBG and TT, but similar FT concentrations during mid and late puberty in parallel with a normal pubertal progression and serum PSA levels. Our data indicate that in obese boys, serum FT concentration is a better marker of androgen activity than TT. On the other hand, skeletal maturation and E2 were increased from the beginning of puberty, suggesting a significant contribution of hyperestrogenemia in the advancement of skeletal maturation in obese boys.

Bone size and bone strength are increased in obese male adolescents.

CONTEXT: Controversy exists on the effect of obesity on bone development during puberty. OBJECTIVE: Our objective was to determine differences in volumetric bone mineral density (vBMD) and bone geometry in male obese adolescents (ObAs) in overlap with changes in bone maturation, muscle mass and force development, and circulating sex steroids and IGF-I. We hypothesized that changes in bone parameters are more evident at the weight-bearing site and that changes in serum estradiol are most prominent. DESIGN, SETTING, AND PARTICIPANTS: We recruited 51 male ObAs (10-19 years) at the entry of a residential weight-loss program and 51 healthy age-matched and 51 bone-age-matched controls. MAIN OUTCOME MEASURES: vBMD and geometric bone parameters, as well as muscle and fat area were studied at the forearm and lower leg by peripheral quantitative computed tomography. Muscle force was studied by jumping mechanography. RESULTS: In addition to an advanced bone maturation, differences in trabecular bone parameters (higher vBMD and larger trabecular area) and cortical bone geometry (larger cortical area and periosteal and endosteal circumference) were observed in ObAs both at the radius and tibia at different pubertal stages. After matching for bone age, all differences at the tibia, but only the difference in trabecular vBMD at the radius, remained significant. Larger muscle area and higher maximal force were found in ObAs compared with controls, as well as higher circulating free estrogen, but similar free testosterone and IGF-I levels. CONCLUSIONS: ObAs have larger and stronger bones at both the forearm and lower leg. The observed differences in bone parameters can be explained by a combination of advanced bone maturation, higher estrogen exposure, and greater mechanical loading resulting from a higher muscle mass and strength.

Male pseudohermaphroditism related to complications at conception, in early pregnancy or in prenatal growth.

We examined whether male pseudohermaphroditism, when unexplained, is associated with reduced prenatal growth. Birth weight SD scores of 29 children with male pseudohermaphroditism were compared. The scores of children with an unexplained condition (median -2.1 SD) were found to be lower (p = 0.0001) than those of children with an explained condition (median -0.4 SD). In the majority of cases of unexplained male pseudohermaphroditism, there was a complicated history before conception or in early pregnancy. In conclusion, hitherto unexplained male pseudohermaphroditism was found to be associated with reduced prenatal growth and complications at conception or in early pregnancy.

A novel TR beta mutation (R383H) in resistance to thyroid hormone syndrome predominantly impairs corepressor release and negative transcriptional regulation.

Resistance to thyroid hormone (RTH) is characterized by elevated serum thyroid hormones, failure to suppress pituitary TSH secretion, and variable T3 responsiveness in peripheral tissues. The disorder is associated with diverse mutations that cluster within three areas of the thyroid hormone beta(TR beta) receptor. Here, we report a novel RTH mutation (R383H), which is located in a region not known to harbor naturally occurring mutations. Although the R383H mutant receptor activated positively regulated genes to an extent comparable to wild-type (WT), negative transcriptional regulation of human TSH alpha and TRH promoters was impaired in either TR beta 1 or TR beta 2 contexts, and WT receptor function was dominantly inhibited. T3-dependent changes in basal transcription with R383H were also impaired: on the TRH promoter, basal activation by unliganded R383H was not reversed by T3 to the same extent as WT; similarly transcriptional silencing by an unliganded Gal4-R383H fusion was not relieved at a T3 concentration that derepressed WT. In keeping with this, ligand-dependent corepressor release by R383H, either in a protein-protein interaction assay or as a DNA-bound heterodimer with retinoid X receptor on either positive or negative thyroid hormone response elements, was disproportionately impaired relative to its ligand-binding affinity, whereas its T3-dependent recruitment of coactivator was unimpaired. These properties were shared by another previously described RTH mutant (R429Q), and in the crystal structure of TR alpha the homologous residues interact in a polar invagination. Our data indicate a role for these residues in mediating negative transcriptional regulation and facilitating corepressor release and suggest that predominant impairment of these functions may be the minimal requirements for causation of RTH.

Growth hormone treatment of short children born small for gestational age.

Short children born small-for-gestational-age (SGA) appear to be at an increased risk of having a poly-endocrinopathy, including a degree of growth hormone (GH) deficiency and/or insulin-like growth factor 1 (IGF-1) resistance. Among GH-deficient children, those born SGA present a lower growth response to GH therapy than those not born SGA. The growth response of short SGA children to GH treatment does not appear to depend significantly on the secretory status of GH (as judged by provocative testing), indicating that the SGA condition (IGF-1 resistance) predominates over the availability of endogenous GH in determining the short stature of the majority of these children. When a higher than replacement dose of GH is administered, the growth response of short SGA children matches that of GH-deficient non-SGA children, indicating that the IGF-1 resistance towards growth can be overcome, and that a normal stature can be obtained, at least throughout childhood. It is anticipated that, increasingly, the indications and the doses for GH therapy in children will become interlinked with the emerging principles of endocrine programming in early life.