Complete androgen insensitivity syndrome coexisting with müllerian duct remnants: a case report and literature review.

This study represents the first documentation of the coexistence of complete androgen insensitivity syndrome (CAIS) with Müllerian duct remnants (MDRs) in mainland China. Additionally, we provide a comprehensive review of the existing literature concerning CAIS with MDRs resulting from androgen receptor (AR) gene mutations. This study broadens the clinical spectrum of CAIS and offer novel insights for further exploration into Müllerian duct regression. A 14-year-old patient, initially raised as female, presented to the clinic with complaints of "primary amenorrhea." Physical examination revealed the following: armpit hair (Tanner stage 2), breast development (Tanner stage 4 with bilateral breast nodule diameter of 7 cm), sparse pubic hair (Tanner stage 3), clitoris measuring 0.8 cm × 0.4 cm, separate urethral and vaginal openings, and absence of palpable masses in the bilateral groin or labia majora. The external genital virilization score was 0 points. Serum follicle-stimulating hormone level was 13.43 IU/L, serum luteinizing hormone level was 31.24 IU/L, and serum testosterone level was 14.95 nmol/L. Pelvic magnetic resonance imaging (MRI) did not reveal a uterus or bilateral fallopian tubes, but nodules on both sides of the pelvic wall indicated cryptorchidism. The karyotype was 46,XY. Genetic testing identified a maternal-derived hemizygous variation c.2359C > T (p.Arg787*) in the AR gene. During abdominal exploration, dysplastic testicles and a dysplastic uterus were discovered. Histopathological analysis revealed the presence of fallopian tube-like structures adjacent to the testicles. The CAIS patient documented in this study exhibited concurrent MDRs, thus expanding the spectrum of clinical manifestations of AIS. A review of prior literature suggests that the incidence of CAIS combined with histologically MDRs is not uncommon. Consequently, the identification of MDRs in AIS cases may represent an integral aspect of clinical diagnosis for this condition.

Clinical characteristics of sitosterolemic children with xanthomas as the first manifestation.

BACKGROUND: Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL. OBJECTIVES: To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas. METHODS: We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL. RESULTS: Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas. CONCLUSION: The xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL.

Therapeutic effects of growth hormone combined with low-dose stanozolol on growth velocity and final height of girls with Turner syndrome.

OBJECTIVE: Turner syndrome (TS), which is characterized by short stature and gonadal dysfunction, is managed by pharmacotherapy. This study aimed to investigate the therapeutic effects of recombinant human growth hormone (rhGH) combined with low-dose stanozolol on the growth and final adult height (FAH) of girls with Turner syndrome (TS). DESIGN: Prospective study. PATIENTS: A total of 44 girls with TS were treated with rhGH (47·6-52·4 µg/kg/day) and low-dose stanozolol (20-35 µg/kg/day), starting at a mean age of 12·65 ± 1·99 year. The control group consisted of 22 girls with TS, who did not receive treatment. MEASUREMENTS: Subjects' growth velocity (GV) was investigated. Height standard deviation score (HtSDS) was calculated relative to healthy Chinese girls (HtSDSN or ) as well as untreated Chinese girls with TS (HtSDSTS ). Post-treatment follow-up was performed until the subjects achieved FAH or near FAH. RESULTS: FAH was significantly higher in subjects receiving treatment compared to the untreated controls (151·42 vs 137·75 cm, P < 0·001). GV was significantly higher in the first to fourth years of treatment compared to baseline values (P < 0·001); it was significantly lower in the second to fourth years of treatment compared to the first year (P < 0·001). CONCLUSIONS: In girls with TS, 9-12 years of age, rhGH combined with low-dose stanozolol may effectively increase growth. At least a 2-year course of this treatment may effectively improve FAH with proper delay of oestrogen-induced development.

Associations between serum apelin-12 levels and obesity-related markers in Chinese children.

OBJECTIVE: To investigate possible correlations between apelin-12 levels and obesity in children in China and associations between apelin-12 and obesity-related markers, including lipids, insulin sensitivity and insulin resistance index (HOMA-IR). METHODS: Forty-eight obese and forty non-obese age- and gender-matched Chinese children were enrolled between June 2008 and June 2009. Mean age was 10.42 ± 2.03 and 10.86±2.23 years in obesity and control groups, respectively. Main outcome measures were apelin-12, BMI, lipids, glucose and insulin. HOMA-IR was calculated for all subjects. RESULTS: All obesity group subjects had significantly higher total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), insulin levels and HOMA-IR (all P<0.05). In separate analyses, obese girls had significantly higher LDL-C, insulin and HOMA-IR than controls, and obese boys had significantly higher TC, TG, insulin and HOMA-IR than controls (all P<0.05). Apelin-12 levels were significantly higher in obese girls compared to controls (P = 0.024), and correlated positively with TG in all obese subjects. Among obese girls, apelin-12 levels correlated positively with TG, insulin and HOMA-IR after adjusting for age and BMI. In all boys (obese and controls) apelin-12 was positively associated with fasting plasma glucose (FPG). No significant correlations were found in either group between apelin-12 levels and other characteristics after adjusting for age, sex, and BMI. CONCLUSIONS: Apelin-12 levels are significantly higher in obese vs. non-obese girls in China and correlate significantly with obesity-related markers insulin, HOMA-IR, and TG. Increased apelin-12 levels may be involved in the pathological mechanism of childhood obesity.

[Effect of gonadotropin-releasing hormone analog combined with stanazolol on final height in girls with idiopathic central precocious puberty and apparent decrease of linear growth].

OBJECTIVE: To evaluate the effect of combined use of stanazolol (ST) on the final adult height (FAH) in girls with idiopathic central precocious puberty (ICPP) and apparently decreased linear growth during gonadotropin-releasing hormone analog (GnRHa) therapy. METHOD: Sixty-three girls with ICPP and decreased velocity of growth of height (HV<4 cm/yr) during GnRHa therapy were divided into 3 groups based on the following types of interventions:group 1 (n = 20), GnRHa+ST [25-30 µg/(kg·d) every 3-month followed by 3-month discontinuation], group 2 (n = 21), GnRHa+recombinant human growth hormone [rhGH, 1-1.1 U/(kg·w)], group 3 (n = 22), GnRHa alone.HV, the advancement of bone age (BA) for chronological age (CA) (ΔBA/ΔCA) and FAH were compared among groups. RESULT: (1)Total duration of ST combination therapy was (12.22 ± 3.62) months, while total duration of combination of rhGH was (13.22 ± 6.80) months. (2)HV increased significantly in both group 1 [ (2.79 ± 0.60) cm/yr vs. (6.27 ± 1.98) cm/yr, P < 0.01] and in group 2 [(2.80 ± 0.50) cm/yr vs. (6.25 ± 1.98) cm/yr, P < 0.01] during combined therapy, but maintained at low levels in group 3 [(3.95 ± 1.10) cm/yr vs. (3.34 ± 0.95) cm/yr, P > 0.05].No significant differences of ΔBA/ΔCA were found among the three groups [0.25(0.11∼0.28), 0.22(0.15∼0.31),0.19(0.10∼0.32), P > 0.05]. (3)FAH was significantly higher than predicted adult height (PAH) before combined therapy, as well as higher than target height (THt) in both group 1 [(156.25 ± 2.90) cm vs. (150.78 ± 3.70) cm, P < 0.01, (156.25 ± 2.90) cm vs. (153.94 ± 2.62) cm, P < 0.01], and in group2 [ (157.33 ± 4.69) cm vs. (152.61 ± 3.92) cm, P < 0.01, (157.33 ± 4.69) cm vs. (154.39 ± 4.72) cm, P = 0.01].In group 3, FAH was similar to PAH [(153.88 ± 2.6) cm vs. (152.54 ± 5.86) cm, P > 0.05], and was less than THt [(153.88 ± 2.6) cm vs. (155.60 ± 4.52) cm, P = 0.02]. (4)In girls treated with ST, no hirsutism, clitorism or hoarse voice was recorded.No polycystic ovary syndrome was found by B-mode ultrasound. CONCLUSION: Intermittent combined use of low dose ST therapy can increase HV and thus improve FAH in girls with ICPP and apparently decreased linear growth during GnRHa therapy.

Insulin resistance and adiponectin levels are associated with height catch-up growth in pre-pubertal Chinese individuals born small for gestational age.

BACKGROUND AND OBJECTIVE: The study was performed to determine whether catch-up growth is associated with the development of insulin resistance and to explore serum endocrine markers associated with the metabolism of adipose tissue in a Chinese population born small for gestational age(SGA) SUBJECTS AND METHODS: We recruited 56 children born SGA with catch-up growth and 55 born without catch-up growth, who were further grouped into groups I (with BMI catch-up) and II (without BMI catch-up) respectively, as well as 52 children born appropriate for gestational age (AGA) with normal height. Their serum fasting insulin, fasting glucose, insulin-like growth factor-1, adiponectin, IGFBP-1, triglyceride concentrations, and the homeostasis assessment model for insulin resistance (HOMA-IR) were evaluated. RESULTS: (1) The HOMA-IR values in SGA-I with catch-up growth group were significantly higher than those in SGA-II with catch-up growth, SGA-I without catch-up growth and AGA children respectively. (2) The serum adiponectin levels of individuals in the SGA-I without catch-up growth and SGA-II with catch-up growth groups were significantly lower than those from the SGA-II without catch-up growth group. There was no difference in triglyceride or IGFBP-1 levels among the groups. (3) The degree of HOMA-IR was positively correlated with age, current BMI and △height SDS in SGA children. CONCLUSION: The development of insulin resistance and lower levels of adiponectin were closely correlated with higher BMI and the postnatal height catch-up growth in SGA children.

Effects of a high-protein diet on insulin resistance and body fat in catch-up growth rats born small for gestational age.

BACKGROUND/AIM: This study was designed to evaluate the effects of a high-protein (HP) diet on insulin resistance and body fat in catch-up growth (CUG) rats born small for gestational age (SGA). METHODS: SGA rats were randomly divided into standard diet and HP diet groups. Perirenal fat weight and blood glucose, serum insulin and insulin-like growth factor-1 levels were measured at 4 and/or 8 weeks. Insulin resistance and ß-cell function were evaluated by homeostatic model assessment for insulin resistance (HOMA-IR) and HOMA%. RESULTS: The values of HOMA-IR in both CUG-SGA groups were significantly higher than those in the appropriate for gestational age (AGA) group (p < 0.01), whereas they were significantly lower in the HP diet CUG-SGA group than in the standard diet CUG-SGA group at week 8 (p < 0.01). At week 8, perirenal fat weight and adipocyte diameters were higher in both CUG-SGA groups than in the AGA group (p < 0.05), but these values were significantly lower in the HP diet CUG-SGA group than in the standard diet CUG-SGA group (p < 0.05). CONCLUSION: The HP diet had positive effects on the prevention of insulin resistance, which may have been caused by the reduction of body fat.

[Determination of serum steroids in monitoring therapy of congenital adrenal hyperplasia].

OBJECTIVE: To assess the utility of serum steroids measurement in monitoring the treatment of children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). METHOD: Nineteen Patients with CAH 21OHD aged (3.67±1.54) years treated with hydrocortisone and fluorocortisone replacement were followed up at an intervals of 0.33 - 1.0 years over a period of (1.47±0.7) years. At each visit, roentgenograms of the hands and wrists were taken, fasting peripheral blood were collected to test serum dehydroepiandrosterone sulfate, progesterone, 17-hydroxyprogesterone (17-OHP), androstenedione (Δ4-A), testosterone, free testosterone, estrone, and estradiol concentrations at 8 AM in the morning before the first dose of glucocorticoid. Then the patients were classified as being in "Good Control" or in "Poor Control" based on clinical criteria including signs of androgen excess, growth velocity and bone age increment at each interval. Comparisons were carried out between the serum steroid concentrations of the two groups. The receiver operating characteristic (ROC) curves were used to determine the cut-off values for diagnosing "Poor Control". RESULT: Both of serum Δ4-A and 17-OHP concentrations were higher in "Poor Control" group than those in "Good Control" group [5.95 (2.23-11.2) nmol/L versus 1.05 (1.05-9.89) nmol/L, t=2.19; 13.85 (6.06-20) µg/L versus 3.67 (0.42-21.1) µg/L, t=2.17; P<0.05, respectively]. The ROC curves for serum Δ4-A concentrations, serum 17-OHP concentrations, serum Δ4-A in combination with 17-OHP concentrations were constructed with areas under the ROC curves (95%CI) of 0.76 (0.62, 0.90), 0.75 (0.62, 0.88), 0.69 (0.54, 0.84), P<0.05, respectively. Serum Δ4-A of 3.9 nmol/L had 0.78 of sensitivity and 0.75 of specificity in diagnosing "Poor Control". Serum 17-OHP of 7.1 µg/L has 0.67 of sensitivity and 0.71 of specificity in diagnosing "Poor Control". CONCLUSION: Each of serum 17-OHP or/and Δ4-A concentration was of significance in diagnosing "Poor Control" during the glucocorticoid replacement treatment of CAH 21OHD, with the diagnostic efficacy being serum Δ4-A concentration, serum 17-OHP concentration and serum Δ4-A in combination with 17-OHP concentration in descending order. Serum Δ4-A and 17-OHP concentrations may be used as the biochemical indicators to monitor the therapy of CAH 21OHD.

[Rapid prenatal genetic diagnosis of a fetus with a high risk for Morquio A syndrome].

OBJECTIVE: To provide rapid and accurate prenatal genetic diagnosis for a fetus with high risk of Morquio A syndrome. METHODS: Based on ascertained etiology of the proband and genotypes of the parents, particular mutations of the GALNS gene were screened at 10th gestational week with amplification refractory mutation system (ARMS), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. RESULTS: DHPLC screening has identified abnormal double peaks in the PCR products of exons 1 and 10, whilst only a single peak was detected in normal controls. Amplification of ARMS specific primers derived a specific product for the fetus's gene, whilst no similar product was detected in normal controls. Sequencing of PCR products confirmed that exons 1 and 10 of the GALNS gene from the fetus contained a heterozygous paternal c.106-111 del (p.L36-L37 del) deletion and a heterozygous maternal c.1097 T>C (p.L366P) missense mutation, which resulted in a compound heterozygote status. CONCLUSION: The fetus was diagnosed with Morquio A syndrome and a genotype similar to the proband. Termination of the pregnancy was recommended. Combined ARMS, DHPLC and DNA sequencing are effective for rapid and accurate prenatal diagnosis for fetus with a high risk for Morquio A syndrome. Such methods are particularly suitable for early diagnosis when pathogenesis is clear. Furthermore, combined ARMS and DHPLC are suitable for rapid processing of large numbers of samples for the identification of new mutations.

Clinical characteristics of adrenocortical tumors in children.

BACKGROUND: Adrenocortical tumors (ACTs) are rare in children. Because of the rarity and various manifestations of ACTs, patients of ACTs are not easily diagnosed. Some patients were misdiagnosed before surgery. OBJECTIVE: Identify the clinical, laboratorial, imaging and histopathological characteristics of adrenocortical tumors in children. Compare adrenalcortical adenoma with carcinoma. METHODS: A retrospective review of 34 identified patients who were younger than 15 years old with histologic confirmation of adrenocortical carcinoma (ACC) or adenomas from 1991 to 2010. RESULTS: In these 34 patients, 19 were adrenocortical adenoma (ACA) and 15 were ACC. The median age at diagnosis was 3.33 years (range, 0-16 years), and 70.6% of the patients were younger than five years. Girls slightly predominated over boys (1.4:1). For endocrine abnormality, 14 patients had isolated precocious puberty, five patients had isolated Cushing syndrome, 10 patients had precocious puberty plus Cushing syndrome, and five patients did not have any symptoms. The most frequent findings in laboratory tests were disturbance of the normal circadian rhythm of cortisol secretion (93.8%), followed by elevated serum level of testosterone (89.7%). Only 3.8% of ultrasound diagnosis and 12.1% of computed tomography (CT) diagnosis were consistent with pathologic diagnosis. CONCLUSION: Different from those in adult, the most frequent presentation in children with ACTs is peripheral precocious puberty with or without Cushing syndrome, and isolated Cushing syndrome. Few present with non-functional local mass. Laboratory tests usually reveal the discordantly elevated serum levels of sexual corticosteroid hormones, change of diurnal rhythm of cortisol or increase of morning cortisol. The differentiation of malignant from benign tumor cannot merely depend on imaging. Final diagnosis relies on comprehensive evaluation of clinical manifestations, laboratory data, imaging and pathology.

Stanozolol regulates proliferation of growth plate chondrocytes via activation of ERalpha in GnRHa-treated adolescent rats.

Improving the final adult height is one of the most important aims for treatment of central precocious puberty. Stanozolol (ST) is a synthetic derivative of androgen. In this study, we investigated the effects and the mechanisms of ST on the proliferation of growth plate chondrocytes isolated from adolescent rats treated with gonadotropin-releasing hormone analogue (GnRHa). Treatment with ST resulted in time- and concentration-dependent effects on proliferation as determined by MTT and proliferating cell nuclear antigen (PCNA) assays. Western blotting showed that ST increased the phosphorylation level of the estrogen receptor alpha (ERalpha), but not the androgen receptor (AR). Pharmacological inhibition of ERalpha and mitogen-activated protein kinase (MAPK) attenuated the effects of ST on the proliferation of growth plate chondrocytes. A molecular dynamics simulation showed hydrophobic interactions between ST and ERalpha. These results suggested that ERalpha, but not AR, partially mediates the ST-driven proliferation of growth plate chondrocytes, and that multiple pathways may be involved in the mechanism of action of ST.

Epidermal growth factor receptor signalling mediates growth hormone-induced growth of chondrocytes from sex hormone-inhibited adolescent rats.

1. Growth hormone (GH) has been demonstrated to overcome the inappropriate deceleration of growth rate in children with central precocious puberty treated with gonadotropin-releasing hormone analogue (GnRHa). However, the underlying mechanisms remain largely unclear. In the present study, we investigated the potential involvement of the epidermal growth factor receptor (EGFR) pathway in the growth promotion by GH using in vitro cultured growth plate chondrocytes isolated from adolescent rats treated with GnRHa. 2. Chondrocytes were stimulated with GH in the presence or absence of the Janus tyrosine kinase (JAK) 2 inhibitor AG490 (1, 10 and 100 nmol/L), the EGFR kinase inhibitor AG1478 (0.1, 1 and 10 nmol/L), U0126 (an inhibitor of extracellular signal-regulated kinase (Erk) activation; 10 µmol/L) or a neutralizing antibody against epidermal growth factor (EGF Ab; 0.1, 1 and 10 µg/mL). The proliferation of chondrocytes was assessed by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and immunostaining for proliferating cell nuclear antigen (PCNA). Phosphorylation of Erk1/2 and EGFR was detected by western-blotting. Intracellular mRNA and extracellular protein levels of EGF were detected using reverse transcription-polymerase chain reaction and ELISA, respectively. 3. Growth hormone promoted the proliferation of chondrocytes, which was correlated with increased phosphorylation of Erk1/2 and EGFR and enhanced expression of EGF. Pretreatment with AG490, AG1478, U0126 or EGF Ab completely or partially inhibited the proliferation of chondrocytes and activation of Erk1/2 and EGFR. Pretreatment with AG490, AG1478, or U0126 partially inhibited the expression of EGF. 4. The findings indicate that GH promotes chondrocyte proliferation by activating EGFR signalling.

Association between height and weight catch-up growth with insulin resistance in pre-pubertal Chinese children born small for gestational age at two different ages.

This study was performed to test whether children born small for gestational age (SGA) with catch-up growth (CUG) could be associated with the early development of insulin resistance and the ß-cell dysfunction and to explore the impacts of height CUG and weight CUG on the insulin resistance in a Chinese population. A total of 30 children born SGA with CUG, 37 non-CUG (NCUG), and 42 born appropriate for gestational age (AGA) with normal height were recruited. Their fasting serum insulin, fasting glucose, insulin-like growth factor-1 (IGF-1) concentrations, and the homeostasis assessment model for insulin resistance (HOMA-IR) and ß-cell function (HOMA%) were evaluated. The values of HOMA-IR in CUG SGA were significantly higher than that in NCUG SGA (P = 0.002) and AGA children (P = 0.036), respectively. Correlation analysis revealed that the concentrations of fasting serum insulin were positively correlated with IGF-1 (r = 0.443, P = 0.001) and Δheight standard deviation score (SDS; r = 0.500, P = 0.002) in ≤ 6-year-old SGA children, but only with Δweight SDS (r = 0.496, P = 0.030) in >6-year-old children. In conclusion, SGA children with CUG in height and a higher body mass index are prone to the development of insulin resistance. Higher levels of insulin were closely correlated with the postnatal height CUG in young SGA children and with the weight CUG in old children.

[Diagnostic value of serum levels of ß-human chorionic gonadotropin (ß-hcG) combined with ß-hcG in cerebrospinal fluid for determining locations of germinomas in children with precocious puberty].

OBJECTIVE: To study the clinical manifestations of germinoma in children with precocious puberty and to evaluate the diagnostic value of serum levels of ß-human chorionic gonadotropin (ß-hcG) combined with detections of ß-hcG in cerebrospinal fluid (CSF). METHOD: Twelve male children with germinomas confirmed by pathology from Jan. 2005 to Dec. 2009, aged from 4.2 to 10.2 years, were enrolled in this study. Patients were classified into two groups according to tumor locations: intracranial group and non-intracranial group. Levels of ß-hcG in serum as well as in CSF were detected before the initiation of therapy. Age and gender matched 5 children undergoing lumbar puncture for other diseases were set as control group for the determinations of ß-hcG in CSF. Levels of ß-hcG and testosterone in serum and CSF were compared between intracranial group and non-intracranial group, and levels of ß-hcG in CSF were compared between non-intracranial group and control group. RESULT: The 12 children showed elevated serum levels of testosterone: 10.43 (1.70-254.00) µg/L, 11 children had testicular volume > 4 ml, while response to LHRH stimulation tests were low; 6 children had gynecomastia. Serum levels of ß-hcG were elevated in both intracranial and non-intracranial group and no significant differences were found between groups 63.75 (8.50-309.50) IU/L vs. 59.00 (25.10-71.77) IU/L, P = 0.644. No correlations were found between serum levels of ß-hcG and ages, tumor locations, and courses of the patients. Levels of ß-hcG in CSF were significantly higher in intracranial group than that in non-intracranial group 488.99 (17.30-1048.53) IU/L vs. 1.20 (1.20-1.50) IU/L, P = 0.009. Children with non-intracranial germinomas had similar levels of ß-hcG in CSF as that in control group (P = 0.571). CONCLUSION: The main clinical manifestations in boys suffered from germinoma included pseudo-precocious puberty, disproportionate testicular volume and gynecomastia. Detection of serum levels of ß-hcG combined with ß-hcG levels in CSF may be useful for determination of the locations of germinomas in children with precocious puberty.

[Longitudinal study of the pattern of pubertal development in Cantonese schoolgirls].

OBJECTIVE: To investigate the pattern of pubertal development in healthy Cantonese schoolgirls. METHOD: From 1992 to 2001, 311 normal Cantonese schoolgirls, ages from 6.25 to 8.83 yrs (7.24 +/- 0.38) at baseline, were followed up until they reached their final adult height (age 15.72 +/- 0.84 yrs, n = 238). Annual physical examinations including height and weight measurement were performed. From the 3rd visit, pubertal maturations (breast and pubic hair development) were also assessed annually until they were 14.5 years. Age of menarche was recorded. RESULT: (1) Median age at the entry of puberty (age at reaching B2) was 9.83 years (9.33-10.33). Median age at initiation of pubic hair development (PH2) was 10.67 (9.92-11.38) years. Menarche occurred at (12.35 +/- 1.30) years. The age at reaching B2, age at reaching PH2 and age of menarche were all later than that observed in the cross-section study performed in 2003, Guangzhou, China. Peak height velocity (PHV) was reached at (10.52 +/- 1.07) years, 1.00 (0.50-1.50) years after B2 was reached. Interval between "age at onset of breast development" and "age at menarche" was 2.92 (2.08-3.67) years. Duration of pubertal growth (defined as the time from age at B2 to age at which adult height was attained) was (4.80 +/- 0.85) years. (2) Average final adult height (FAH) was (158.74 +/- 5.74) cm. As compared with the cross-section studies held in Guangzhou, China, the FAH in our study was higher than that observed in 1985 but was lower than that observed in 2003. (3) Multiple linear regression analyses showed that the age reaching B2 was an independent factor associated with the age of menarche. (4) Durations of breast stages, interval between B2 and menarche and duration of pubertal growth were similar to that reported in the longitudinal studies in the United Kingdom (1969), Senegal (1995-2000), the United States (1986-1996). CONCLUSION: In healthy Cantonese schoolgirls, the timing of sexual maturation was in a trend of decline in the past 20 years, however it may have no significant impacts on the tempo of pubertal development and FAH.

[Stanozolol activates the cross-talk of estrogen receptor alpha-insulin-like growth factor-1 receptor-extracellular-signal regulated kinase 1/2 in the growth plate chondrocytes of estrogen-inhibited adolescent rats in vitro].

OBJECTIVE: To investigate the effects and the mechanisms of stanozolol (ST) on the proliferation, maturation and differentiation of in vitro cultured growth plate chondrocyte isolated from gonadotropin releasing hormone analogue (GnRHa)-treated adolescent rats, to study if ST mediates the proliferation of chondrocytes via the estrogen receptor alpha (ERalpha), androgen receptor (AR) and/or insulin-like growth factor-1 receptor (IGF-1R) and interactions of the two receptor and IGF-1R receptor signaling pathway, to investigate the mechanism of the biological effects in ST promoting bone growth/maturity at molecular level. METHOD: The rats were weaned at the end of 3 weeks and intramuscular injection of triptorelin of GnRHa preparations, qow x 2 was started. The rats were sacrificed at the end of 7 weeks, and then the tibiae growth plates were taken out with sterile procedure. The chondrocytes were obtained by two-time enzyme digestion method, and the experiments were carried out with the primary chondrocytes. Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) and Western blot analysis were applied. RESULT: The results of PCNA demonstrated that stanozolol enhanced the proliferation of the chondrocytes, time-course studies showed that the proliferation were maximally stimulated by stanozolol after 2 days of incubation and decreased again after longer periods of incubation. The expression of p-ERalpha, p-IGF-1R and p-extracellular-signal regulated kinase 1/2 (ERK1/2) increased with the incubation period of ST treatment, and reached the peak value at a certain time, and then gradually decreased. The expression of p-ERalpha, p-IGF-1R and p-ERK1/2 increased with the elevation of ST concentration, and reached the peak value at 10(-9) - 10(-8) mol/L, then gradually decreased. ST induced-p-ERalpha expression was partially blocked by ERalpha and mitogen-activated protein kinase kinase inhibitors. ST induced-p-IGF-1R expression was partially blocked by ERalpha and IGF-1R inhibitors. ST induced-p-ERK1/2 expression was partially blocked by mitogen-activated protein kinase kinase and IGF-1R inhibitors. CONCLUSION: As an androgen derivation, ST exerts its biological effects of promoting proliferation of the long bone growth plate chondrocytes via activating the classic ERalpha receptor pathway and mitogen-activated protein kinase pathway, and at the same time, by activation of IGF-1R. Both IGF-1R and ERalpha can promote "cross-talk" of two systems' receptor signal through mitogen-activated protein kinase signal pathway.

Onset of breast and pubic hair development and menses in urban chinese girls.

OBJECTIVES: To determine the current prevalence and mean ages of onset of pubertal characteristics in healthy urban Chinese girls. METHODS: A cross-sectional study of sexual maturation of healthy Chinese girls was conducted in 9 representative cities of the eastern, western, southern, and northern parts and central region of China between 2003 and 2005. At examination, stages of breast and pubic hair development were rated on girls 3 through 19.83 years of age, and height and weight were also recorded. Data on menses were collected by the status quo method. Probit analysis was used to calculate the median age and 95% confidence interval (CI) for onset of breast and pubic hair development and menarche. RESULTS: Data were analyzed for 20654 apparently healthy girls. At age 8 years, 19.57% of these girls had evidence of breast development. The median ages of onset of Tanner stages 2 and 3 for breast development were 9.20 (95% CI: 9.06-9.32) years and 10.37 (95% CI: 10.28-10.45) years, respectively. The median ages of onset of Tanner stages 2 and 3 for pubic hair development were 11.16 (95% CI: 11.03-11.29) years and 12.40 (95% CI: 12.25-12.55) years, respectively. Menses occurred at 12.27 years (95% CI: 12.16-12.39). CONCLUSIONS: These data suggest that urban Chinese girls are actually experiencing earlier breast development than currently used norms. The up-to-date reference for normal pubertal development in urban Chinese girls needs to be established for the purpose of determining precocious puberty or pubertal delay.

[Efficacy and safety of recombinant human growth hormone solution in children with growth hormone deficiency in China: a multicenter trial].

OBJECTIVE: Human growth hormone (hGH) is an essential therapeutic drug for the treatment of growth hormone (GH) deficiency (GHD). However, the process of dissolving hGH of the powder form is complicated and potentially hazardous. In the present study, we evaluated the efficacy and safety of preparation in the replacement therapy for children with GH deficiency. METHODS: A 12-month randomized, open-label, multicenter trial was conducted in 31 previously untreated children with growth failure secondary to GH deficiency [20 boys and 11 girls, mean age (10.5 +/- 4.1) years]. An recombined human growth hormone (rhGH) solution (Iintropin AQ) was given via subcutaneous injection daily in every evening at a weekly dose of 0.25 mg/kg. The patients were followed up at 3, 6, 9, and 12 months of the treatment, and the course of treatment was 12 months. Body height was measured 3-monthly and height velocity (HV) and mean height standard deviation score (HT SDS) were calculated. Serum Insulin-like growth factor I (IGF-1), Insulin-like growth factor binding protein 3 (IGFBP-3), GH antibodies and safety parameters were assessed at the baseline and at 3-month intervals. Bone age (BA) was assessed at the baseline and the rate of skeletal maturation (DeltaBA/DeltaCA) was calculated after 6 and 12 months of rhGH treatment by a central bone age reader. Moreover, the safety of rhGH solution treatment was assessed. RESULTS: After 12 months of liquid rhGH therapy, growth parameters were significantly increased over baseline. (1) The mean (+/- SD) height increment DeltaHT (cm) was 4.0 +/- 1.3, 7.0 +/- 2.0, 10.3 +/- 2.6 and 12.9 +/- 3.3 after 3, 6, 9, and 12 months of treatment, respectively (P < 0.01), which indicated linear growth after treatment. The GV (cm/years) was 2.7 +/- 0.9 before treatment and increased to 16.0 +/- 5.1, 14.1 +/- 4.0, 13.7 +/- 3.5, and 12.9 +/- 3.3 after treatment, suggesting that catch-up growth was significant after treatment as compared to the pre-treatment status (P < 0.01). Accordingly, post-treatment catch-up growth was obvious, significant differences were observed in HT SDS, which was -4.62 +/- 1.46 at the onset of therapy and increased significantly after the treatment to -3.80 +/- 1.53, -3.28 +/- 1.60, -2.86 +/- 1.75 and -2.47 +/- 1.86, respectively (P < 0.01). The height difference between GH deficient children and unimpaired children of the same age and gender gradually decreased after treatment, which was significantly different from that seen before treatment (P < 0.01). (2) The levels of serum IGF-1 and IGFBP-3 were increased comparably for the treatment. IGF-1 level (microg/L) was 41 +/- 64 at baseline and increased to 179 +/- 155, 202 +/- 141, 156 +/- 155 and 159 +/- 167 after 3, 6, 9, 12 months of treatment. IGFBP-3 level (mg/L) was 1540 +/- 1325 at baseline, and increased to 3891 +/- 1815, 4051 +/- 1308, 3408 +/- 1435 and 3533 +/- 1413, respectively, suggesting that with the increases in height, IGF-1, and IGFBP-3 were significantly activated to relatively high levels by the medication and reached peak values between 3 and 6 months of treatment. The levels of IGF-1 and IGFBP-3 were significantly different before and after treatment (P < 0.01). The IGF-1/IGFBP-3 molar ratio significantly increased during GH therapy (0.143 +/- 0.013 pre-therapy up to 0.240 +/- 0.055 post-therapy, P < 0.01). The IGF-1/IGFBP-3 molar ratio tended to stabilize after 3-month GH therapy. (3) The bone age assessment carried out 6 and 12 months after treatment showed that the bone maturity (DeltaBA/DeltaCA) was 1.01 +/- 0.57 and 1.07 +/- 0.75, respectively, suggesting that there was no speed-up development in the bone age. No severe adverse events were observed during the trial and the most frequent accompanying event was mild hypothyroidism. CONCLUSIONS: rhGH solution (Iintropin AQ) is a safe and effective preparation in the replacement therapy for children with GH deficiency.

[Establishment and validation of predictive model of short term responses to recombinant human growth hormone treatment in prepubertal short stature children with various growth hormone secretary statuses].

UNLABELLED: It has been proved that to analyze the factors that determine responsiveness to rhGH and to develop growth prediction models can help doctors to individualize the treatment and maximize the effect. OBJECTIVES: To set up and validate the predictive models of growth responses to rhGH treatment in the first year in prepubertal short stature children with various GH secretary statuses. METHODS: Growth responses to rhGH treatment in the first year, height velocities (HV) and increases in height SDS (DeltaHtSDS), in 62 prepubertal short stature children with various GH secretary statuses were analyzed retrospectively. There were 27 patients with complete growth hormone deficiency (cGHD), 23 with partial GHD (pGHD) and 12 with idiopathic short stature (ISS) in the model group. According to the peak GH value in GH provocative test, the group of pGHD was divided into pGHD-1 (5 - 6.9 microg/L, 12 patients) and pGHD-2 (7 - 9.9 microg/L, 11 patients). All the cases in model group were used for setting up Model-total and the cases of growth hormone deficiency for Model-GHD. Predictive models, including Model-GHD and Model-total, to HV and DeltaHtSDS were set up by the way of multiple regression analysis, based on the results of simple correlation analysis. Other 14 children were included according to the same criteria with the model group, the validation group. The validation group was analyzed prospectively. The actual growth responses were compared with the predicted values calculated by different models so that the predictive models could be validated. RESULTS: The simple correlation analysis showed that HV and DeltaHtSDS in the first year were negatively correlated with the same group factors at baseline: chronological age, bone age, height SDS, differences between the height SDS and the target height SDS, peak value in GH provocative test and IGF-1SDS. All the 4 predictive models were found to be significant at a level of P < 0.05, R(2) ranged from 0.244 to 0.519. The two models predicted HV and Model-GHD for DeltaHtSDS were proved to be validated. The observed and predicted responses positively and significantly correlated with each other, r value ranged from 0.753 to 0.996. And there was no significant difference between them when tested by paired t test. CONCLUSIONS: The availability of the predictive model will help to individualize the growth hormone treatment in prepubertal short stature children with various growth hormone secretary status.

[Correlation between growth hormone/insulin-like growth factor-1 resistance and insulin resistance in non catch-up growth rats born small for gestational age].

OBJECTIVE: To investigate the post-receptor signaling mechanism responsible for insulin resistance-induced growth hormone (GH) resistance in non-catch-up (NCU) growth rats born small for gestational age (SGA). METHODS: Twenty pregnant female SD rats were fed with restricted food (40% of normal intake, 9 g/d) throughout the pregnancy so as to develop NCU-SGA rats. The rats with their length and body weight < or = -2SD were out into the NCU-SGA group, and those with their length and body weight > -2SD were out into the catch-up (CU) growth group. Rats born to normally-fed pregnant rats were set as normal control (control Group, C Group, n = 17). The body weight and length were measured every 2 weeks. At the age of 4 weeks, 24 h urine was collected to measure the urine GH (U-GH). Then blood samples were collected to measure the serum insulin-like growth factor-1 (IGF-1), fasting insulin (FINS), and glucose levels, and the liver was taken out to detect the expression of STAT5 signal. Twelve 3-week NCU-SGA rats were divided into 2 equal groups: P13K blocking group, undergoing intraperitoneal injection of LY294002, blocker of P13K twice every 3 days, and solvent control group, undergoing intraperitoneal injection of DMSO. At the age of 4 weeks, blood samples were collected and then the liver was taken out to detect the IGF-1 mRNA and STAT5 signal. RESULTS: (1) The body weight and length at birth of the NCU-SGA group were (4.4 +/- 0.5) g and (4.5 +/- 0.2) cm, both significantly lower than those of Group C [(6.8 +/- 0.6) g and (5.3 +/- 0.2) cm respectively], and the body weight and length at 4 weeks of age of the NCU-SGA group were (63 +/- 12) g and (13.2 +/- 1.0) cm respectively, both significantly lower than those of the C group [(88 +/- 12) g and (15.3 +/- 0.5) cm respectively, all P < 0.01]. The serum IGF-1 level, IGF-1 mRNA expression, and total and phosphate STAT5 level in liver of the NCU-SGA group were (248 +/- 58) ng/ml, (6.1 +/- 0.3) copies, and (61 +/- 22)% respectively, all significantly lower than those of the C group [(383 +/- 62) ng/ml, (6.6 +/- 0.4) copies, and (91 +/- 29)%, all P < 0.01]. There was no statistic difference in 24 h U-GH between the NCU-SGA and C groups (P > 0.05). The FINS and glucose level of the NCU-SGA group were (24.7 +/- 9.6) mU/ml and (5.4 +/- 0.3) mmol/L respectively, both significantly higher than those of the C group [(9.8 +/- 2.8) mU/ml and (4.5 +/- 1.7) mmol/L respectively, both P < 0.05]. The level of 24 h U-GH was positively correlated with FINS (r = 0.680, P = 0.000). No correlation was found between IGF-1 and fasting insulin level. (2) After the PI3K pathway was chronically blocked, the NCU-SGA rats lost weight and developed a more severe insulin resistance, decreased serum IGF-1 level and the IGF-1 mRNA expression level of the PI3K inhibitor group were (218 +/- 60) ng/ml and (6.1 +/- 0.3) copies respectively, both significantly lower than those of the solvent control group [(286 +/- 45) ng/ml and (6.3 +/- 0.3) copies, both P < 0.05]. No statistically significant difference in total and phosphate STAT5 levels in liver between the P13K blocker and solvent groups. CONCLUSION: GH resistance is closely associated with insulin resistance in the NCU-SGA rats. GH resistance-induced failure of catch-up growth is related to the impairment of JAK2-STAT5 pathway. Insulin resistance exacerbates growth axis resistance and growth retardation in NCU-SGA rats via a non-STAT5 dependent pathway.