Retrospective evaluation of metformin and/or metformin plus a new polysaccharide complex in treating severe hyperinsulinism and insulin resistance in obese children and adolescents with metabolic syndrome

Background: Pharmacological treatment of obesity and glucose-insulin metabolism disorders in children may be more difficult than in adults. Thus, we evaluate the effects of metformin in comparison with metformin plus a polysaccharide complex (Policaptil Gel Retard®, PGR) on body weight and metabolic parameters in obese children and adolescents with metabolic syndrome (MetS). Patients and methods: We retrospectively collected 129 children and adolescents (67 girls, 62 boys; median age 12.6 years) treated for a minimum of two years with metformin and low glycemic index (LGI) diet. Of these, 71 patients were treated with metformin plus PGR after at least 12 months of metformin alone. To minimize the confounding effect of the LGI on auxological and metabolic parameters, the patients were compared with age-, sex-, and BMI-matched control group with obesity and MetS (51 subjects; 24 males, 27 females) treated only with a LGI diet. Assessments included lipids, glucose and insulin (fasting and after oral glucose tolerance test) concentrations. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Matsuda, insulinogenic and disposition indices were calculated. Results: Metformin treatment led to a significant reduction in BMI SDS (p < 0.0001), with a significant difference in ΔBMI SDS between patients and controls (p < 0.0001). Moreover, metformin treated patients showed a reduction in HOMA-IR (p < 0.0001), HbA1c levels (p < 0.0001) and a significant increase in Matsuda index (p < 0.0001) in respect to the reduction discovered in controls (p < 0.05). Moreover, in contrast to the group treated with metformin alone and controls, patients treated with metformin plus PGR showed a further reduction in BMI SDS (p < 0.0001), HOMA-IR (p < 0.0001), HbA1c (p < 0.0001), total, HDL and LDL cholesterol (p < 0.0001), as well as an increase in Matsuda (p < 0.0001), disposition (p < 0.005) and insulinogenic (respectively, p < 0.05 and p < 0.0001) indices. Conclusions: Metformin appears to show short-term efficacy in reducing BMI, adiposity and glucose and insulin parameters in obese children and adolescents with MetS. However, PGR added to metformin may be useful to potentiate weight loss and to improve glucose-insulin metabolism and adiposity parameters in these patients

RESULTS OF TREATMENT WITH TESTOSTERONE ENANTHATE IN 7 CASES OF MICROPENIS

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Nitric oxide synthase-dependent NADPH-diaphorase activity in the optic lobes of male and female Ceratitis capitata mutants

Nitric oxide (NO) is acknowledged as a messenger molecule in the nervous system with a pivotal role in the modulation of the chemosensory information. It has been shown to be present in the optic lobes of several insect species. In the present study, we used males and females from four different strains of the medfly Ceratitis capitata (Diptera, Tephritidae): or; or,wp (both orange eyed); w,M360 and w,Heraklion (both white eyed), as models to further clarify the involvement of NO in the mutants' visual system and differences in its activity and localization in the sexes. Comparison of the localization pattern of NO synthase (NOS), through NADPH-diaphorase (NADPHd) staining, in the optic lobes of the four strains, revealed a stronger reaction intensity in the retina and in the neuropile region lamina than in medulla and lobula. Interestingly, the intensity of NADPHd staining differs, at least in some strains, in the optic lobes of the two sexes; all the areas are generally strongly labelled in the males of the or and w,M360 strains, whereas the w,Heraklion and or,wp mutants do not show evident sexdependent NADPHd staining. Taken as a whole, our data point to NO as a likely transmitter candidate in the visual information processes in insects, with a possible correlation among NOS distribution, eye pigmentation and visual function in C. capitata males. Moreover, NO could influence behavioural differences linked to vision in the two sexes

Noonan syndrome and related disorders: Alterations in growth and puberty

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548–555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465–468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652–662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413–427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42–48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038–1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet,2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294–296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis

TESTICULAR RESPONSIVENESS TO A SINGLE HCG DOSE IN PATIENTS WITH TESTICULAR FEMINIZATION

The suggestion that androgens may regulate testosterone (T) production in rat Leydig cells by a receptor-mediated feed-back mechanism, led us to investigate whether in vivo the absence of testicular androgen receptors, as it occurs in testicular feminization (TF), may modify the characteristic testicular response observed in men and prepubertal children after a single dose of hCG. Subjects consist of: 1) six normal men, 2) two adult patients with the complete form of androgen insensitivity syndrome (TF), 3) 12 normal prepubertal boys, 4) one prepubertal boy with the same form of TF. Each subject received i. m. a single dose of hCG 3500 IU/m2 b. s. and blood samples were collected basally and 2, 4, 24, 48, 72 and 96 hours after the hormonal stimulus. Serum levels of T, 17α hydroxyprogesterone (17OHP) and 17β estradiol (E2) were measured at each collection time. In normal men a significant increase in T (M ± SE) was observed at 4 h (758.6 ± 135 ng/dl, P < 0.05) and a more significant increase at 48 h (1082 ± 60.3 ng/dl, P < 0.001). E2 and 17OHP peaked significantly at 24 h (81.5 ± 9.6 pg/ml and 460.7 ± 90.9 ng/dl respectively). This response pattern is characteristic of the testicular desensitization which occurs in normal man after a single hCG dose. The same response pattern has been observed in the two TF adult patients suggesting that human testicular desensitization in vivo does not depend on androgen receptors. In normal prepubertal boys there was a slow and progressive increase in T which reached the value of 177 ± 8.7 ng/dl (P < 0.001) at 48 h and remained stable for an additional 48 hours. Plasma E2 and 17OHP did not change after hCG stimulation. The prepubertal patient with TF showed the same response. This finding further seems to exclude any possible role of androgen receptors in testicular response to hCG also in prepubertal age

RESULTS OF TREATMENT WITH TESTOSTERONE ENANTHATE IN 7 CASES OF MICROPENIS

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Spontaneous pubertal development in Turner's syndrome

The incidence of spontaneous puberty in Turner's syndrome is reported to be between 5-10% and, more recently in some series, as high as 20%. In an Italian retrospective multicenter study, of 522 patients older than 12 yr with Turner's syndrome, 84 patients (16, 1%) presented spontaneous pubertal development with menarche that occurred at a chronological age of 13.2 +/- 1.5 yr (mean +/- SD) and a bone age of 12.9 +/- 1.9 yr. Karyotype distribution in the whole group was as follows: 52.1% (272 patients) X-monosomy (45,X), 13.2% (69 patients) mosaicism characterized by X-monosomy and cellular line with no structural abnormalities of the second X, 19.9% (104 patients) mosaicism characterized by X-monosomy and cellular line with structural abnormalities of the second X, and 14.8% (77 patients) structural abnormalities of the second X. Menstrual cycles were still regular in 30 patients at 9.2 +/- 5.0 yr after menarche, 12 developed secondary amenorrhea 1.6 +/- 2.0 yr after menarche, and 19 had irregular menstrual cycles 0.9 +/- 1.8 yr after menarche. As signs of spontaneous puberty developed in 14.0% of X-monosomic patients and in 32.0% of patients with cell lines with more than one X, the presence of the second X stems to have a cardinal influence on the appearance of spontaneous puberty. Spontaneous pregnancy occurred in 3 patients (3.6%). The presence of chromosomal abnormalities and malformations in 2 of 3 pregnancies lad us to agree with other investigators in discouraging unassisted pregnancies. Treatment with GH does not seem to exert any influence on either the age of onset or the prevalence of spontaneous pubertal development in Turner's syndrome. The increased percentage of spontaneous menarche is Turner's syndrome reported in the recent literature might be due to increased ascertainment by diligent screening for Turner's syndrome in girls with short stature and mild or no Turner's syndrome stigmata, even though they may be menstruating

Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome

The incidence of spontaneous puberty in Turner's syndrome is reported to be between 5-10% and, more recently in some series, as high as 20%. In an Italian retrospective multicenter study, of 522 patients older than 12 yr with Turner's syndrome, 84 patients (16, 1%) presented spontaneous pubertal development with menarche that occurred at a chronological age of 13.2 +/- 1.5 yr (mean +/- SD) and a bone age of 12.9 +/- 1.9 yr. Karyotype distribution in the whole group was as follows: 52.1% (272 patients) X-monosomy (45,X), 13.2% (69 patients) mosaicism characterized by X-monosomy and cellular line with no structural abnormalities of the second X, 19.9% (104 patients) mosaicism characterized by X-monosomy and cellular line with structural abnormalities of the second X, and 14.8% (77 patients) structural abnormalities of the second X. Menstrual cycles were still regular in 30 patients at 9.2 +/- 5.0 yr after menarche, 12 developed secondary amenorrhea 1.6 +/- 2.0 yr after menarche, and 19 had irregular menstrual cycles 0.9 +/- 1.8 yr after menarche. As signs of spontaneous puberty developed in 14.0% of X-monosomic patients and in 32.0% of patients with cell lines with more than one X, the presence of the second X seems to have a cardinal influence on the appearance of spontaneous puberty. Spontaneous pregnancy occurred in 3 patients (3.6%). The presence of chromosomal abnormalities and malformations in 2 of 3 pregnancies led us to agree with other investigators in discouraging unassisted pregnancies. Treatment with GH does not seem to exert any influence on either the age of onset or the prevalence of spontaneous pubertal development in Turner's syndrome. The increased percentage of spontaneous menarche is Turner's syndrome reported in the recent literature might be due to increased ascertainment by diligent screening for Turner's syndrome in girls with short stature and mild or no Turner's syndrome stigmata, even though they may be menstruating

Combined treatment with gonadotropin-releasing hormone analog and growth hormone in central precocious puberty

GnRH analogs (GnRHa) arrest pubertal development and slow growth velocity (GV) and bone maturation, thus improving adult height in central precocious puberty (CPP). In some patients, however, GV decreases to such an extent that it compromises the improvement in predicted adult height (PAH). Fourteen children (10 girls and 4 boys) with idiopathic CPP whose GV during GnRHa treatment decreased below the 25th percentile for chronological age with no improvement in PAH received GH at a dose of 0.3 mg/kg . week, sc, 6 days/week for 2-3 yr. Fourteen children (10 girls and 4 boys) with idiopathic CPP, matched for bone age IBA), chronological age, and duration of GnRHa treatment, who showed the same growth deceleration but refused GH treatment, served as the control group. In girls, GV as so score for BA improved from -3.4 +/- 0.5 to -2.5 +/- 0.5 after 3 yr of combined treatment; PAH significantly improved from 152.7 +/- 1.7 cm (before GnRHa) and 153.5 +/- 1.7 cm (before GnRHa and GH) to 167.1 +/- 3.0 cm after 3 yr of combined treatment (P < 0.01 us. pretreatment with GnRHa plus GH). In boys, GV as SD score for BA remained unchanged from -2.0 +/- 1.0 to -2.2 +/- 1.2 after 2 yr of combined treatment; PAH increased from 166.6 +/- 4.8 cm (before GnRHa) and 166.2 +/- 4.9 (before GnRHa plus GH) to 171.1 +/- 6.1 cm after 2 yr (P = NS). In the control group, in girls after 6 yr of GnRHa treatment, height in so score for BA improved from -1.0 +/- 0.3 to -0.1 +/- 0.4 (P = NS), and PAH significantly improved from 155.5 +/- 2.0 to 161.5 +/- 2.1 cm (P < 0.05); in boys after 4 yr of GnRHa treatment, height in so score for BA improved from -1.1 +/- 0.3 to -0.3 +/- 0.4 (P = NS), and PAH changed from 172.6 +/- 3.6 to 170.3 +/- 3.6 cm (P = NS). Eight of 10 girls receiving GH plus GnRHa treatment had an actual height higher than PAH and their target height. The results of our long term study indicate that in children with CPP who show a marked decrease in GV during GnRHa treatment, GH administration remarkably improves growth velocity and predicted adult height, especially in girls