Corneal involvement in Graves' orbitopathy : an in vivo confocal study

PURPOSE: To study the clinical involvement of the ocular surface and the in vivo morphology of corneal cells and nerves, in patients affected by active and inactive Graves' orbitopathy (GO). METHODS: The study included 26 consecutive GO patients and 20 age- and sex-matched healthy control subjects. GO was diagnosed on the basis of the criteria of the European Group on Graves' Orbitopathy, and disease activity was evaluated by the Clinical Activity Score (CAS). Each participant underwent a full eye examination, including an evaluation of symptoms (Ocular Surface Disease Index score), tear break-up time, fluorescein and lissamine green staining, corneal apex sensitivity, and Schirmer's test. The corneal apex was examined by means of confocal microscopy to investigate the number and morphology of epithelial and stromal corneal cells and subbasal nerves. RESULTS: Eleven (43%) of the 26 patients had active GO. One-way ANOVA with the least-significant difference (LSD) post hoc test revealed statistically significant differences between patients and controls in all the evaluated parameters, except corneal sensitivity and nerve reflectivity. Among the GO patients, the only significant difference observed in active compared with inactive disease was in the number of hyperreflective (activated) keratocytes (P<0.001, LSD). Corneal sensitivity correlated inversely with proptosis (P<0.001, Spearman's test). CONCLUSIONS: GO patients show clinical and confocal corneal alterations and signs and symptoms partially related to dry eye disease. The ocular surface inflammation in GO seems to be due to both the dry eye and the autoimmune orbitopathy

Pseudohypoparathyroidism and GNAS epigenetic defects : clinical evaluation of Albright hereditary osteodystrophy and molecular analysis in 40 patients

Context: The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, whereas PHP-Ib patients do not have AHO, and hormone resistance appears to be limited to PTH and TSH. Recently, methylation defects have been detected in few patients with PHP and mild AHO, indicating a molecular overlap between the two forms. Objectives: The aim of the study was to screen patients with clinically diagnosed PHP-Ia for methylation defects and to investigate the presence of correlations between the molecular findings and AHO severity. Patients and Methods: We investigated differential methylation of GNAS regions and STX16 microdeletions in genomicDNAfrom 40 patients with sporadicAHOand multihormone resistance, with no mutations in Gs -coding GNAS exons. Results: Molecular analysis showed GNAS cluster imprinting defects in 24 of the 40 patients analyzed. NoSTX16 deletion was detected. The presence of imprinting defects was not associated with the severity of AHO or with specific AHO signs. Conclusions: We report the largest series of the literature of patients with clinical AHO and multihormone resistance and no mutation in the Gs gene. Our findings of frequent GNAS imprinting defects further confirm the existence of an overlap between molecular and clinical features of PHP-Ia and PHP-Ib and highlight the necessity of a new clinical classification of the disease that takes into account the recent knowledge on the molecular basis underlying these defects

Hypergonadotropic Ovarian Failure Associated with an Inherited Mutation of Human Bone Morphogenetic Protein-15 (BMP15) Gene

Hypergonadotropic ovarian failure is a common cause of female infertility. It is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis (OD). Most OD cases are associated with major Xchromosome abnormalities, but the pathogenesis of this disorder is still largely undefined in patients with a normal karyotype. Animal models showed the important role in female reproduction played by the product of a gene located at Xp11.2 in humans (BMP15). BMP15 is an oocyte-specific growth/differentiation factor that stimulates folliculogenesis and granulosa cell (GC) growth. We report two sisters with a normal karyotype who are affected with hypergonadotropic ovarian failure due to OD. The familial presentation suggested a genetic origin, and candidate genes were screened for mutations. A heterozygous nonconservative substitution in the pro region of BMP15 (Y235C) was identified in both sisters but not in 210 control alleles. This mutation was inherited from the father. Mutant BMP15 appears to be processed abnormally, is associated with reduced GC growth, and antagonizes the stimulatory activity of wild-type protein on GC proliferation. In conclusion, the first natural mutation in human BMP15 is associated with familial OD, indicating that the action of BMP15 is required for the progression of human folliculogenesis. This condition represents an exceptional example of X-linked human disease exclusively affecting heterozygous females who inherited the genetic alteration from the unaffected father. BMP15 defects are involved in the pathogenesis of hypergonadotropic ovarian failure in humans

The natural history of the hyperthyrotropinemia of children born prematurely

Objective: Non-autoimmune hyperthyrotropinemia has been previously reported among children born prematurely. The aim of this study was to follow up their thyroid function, volume, and structure and to investigate the relationship with growth, IGF-I, lipid profile, and insulin sensitivity. Methods: Seventy-two children born prematurely (33.2 +/- 2.2 weeks), 26 appropriate (AGA) and 46 small for gestational age (SGA), were evaluated at the age of 7.6 +/- 2.3 yr (time 1) and at the age of 11.4 +/- 2.3 yr (time 2). We also measured TSH, free T-3 (fT(3)), free T-4 (fT(4)), thyroperoxidase antibodies (TPO-Ab), thyroglobulin antibodies (TG-Ab), thyroid ultrasound, auxological parameters, lipid profile, glucose, and insulin level. Results: In the AGA group TSH was similar in both times (2.7 +/- 1.0 vs 3.0 +/- 0.9 mU/l) and above the upper normal limit in 4 (15.4%) subjects at time 1 and in 6 (23.7%) subjects at time 2 (ns). In the SGA group, TSH was similar in both times (2.8 +/- 1.2 vs 2.5 +/- 1.0 mU/l) and above the upper normal limit in 11(23.9%) subjects at time 1 and 5 (10.8%) subjects at time 2 (ns). fT(4) and fT(3) were always normal and TPO- and TG-Ab absent. Thyroid volume increased progressively, but significantly only in the AGA group (p=0.0005). The thyroid structure was always normal and there was no influence on the growth and the biochemical profile. Conclusions: Some ex-premature babies show a mild and variable thyroid dysfunction, which does not seem to evolve toward an overt thyroid dysfunction

Circulating levels of growth hormone, insulin-like growth factor-I and prolactin in normal, growth retarded and anencephalic human fetuses

We measured growth hormone (GH), insulin-like growth factor-I (IGF-I), and both total and glycosylated prolactin (PRL) levels in 131 blood samples obtained by cordocentesis in normal and abnormal fetuses from 19 to 40 weeks of gestation. In normal fetuses, IGF-I and PRL levels showed a positive correlation and GH a negative correlation with gestational age. A negative relation between GH and IGF-I levels was observed, while PRL did not show any correlation with both GH and IGF-I concentrations. IGF-I increased from 5.6 +/- 3 (at 19-22 weeks) to 10.7 +/- 5 nmol/l at term; GH decreased from 31 +/- 10 to 7.7 +/- 4 micrograms/l and PRL increased from 16 +/- 18 to 139 +/- 76 micrograms/l. Glycosylated PRL accounted for about 15% of total PRL, a value similar to that found in normal adults. In 27 fetuses of 27-37 weeks with intra-uterine growth retardation, GH and PRL levels were higher and IGF-I levels lower than in normal fetuses matched for week of gestation. In 8 anencephalic fetuses of 19-26 weeks of gestation, both GH and IGF-I levels were lower, and PRL levels were higher than in matched controls. Altogether these data support the views that a) both GH and PRL secretion are under the hypothalamic control during fetal development, b) the serum GH decrease from midgestation to the end of pregnancy is mediated by the negative feed-back mechanism of increasing IGF-I levels and c) IGF-I production is mainly regulated by fuel supply and only partially by GH

Different effects of short- and long-term recombinant hGH administration on ghrelin and adiponectin levels in GH-deficient adults

OBJECTIVE: To evaluate circulating levels of ghrelin and adiponectin (ApN) in GH-deficient (GHD) adults before and after short- and long-term recombinant human GH (rhGH) administration. PATIENTS AND METHODS: Twenty-three patients were studied. Seventeen subjects (Group A, 12 men, five women) were evaluated at baseline and after 1 year rhGH therapy (dose mean +/- SD: 0.3 +/- 0.1 mg/day) with the assessment of serum IGF-I, ghrelin, ApN, leptin, insulin and glucose levels, percentage of body fat (BF%), HOMA-IR and QUICKI. Seventeen age-, sex- and body mass index (BMI)-matched healthy subjects were recruited for comparisons. Six patients (Group B, three men, three women) underwent IGF-I generation test (rhGH 0.025 mg/kg/day for 7 days), blood sampled at baseline and on day 8 for determination of IGF-I, ghrelin and ApN levels. RESULTS: Group A: at baseline GHD patients showed low IGF-I levels and BF% significantly higher than controls (31.4 +/- 2.5 vs. 26.4 +/- 1.3, P < 0.05). Glucose, insulin, leptin, tryglicerides, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as HOMA-IR and QUICKI values were similar in the two series, while total cholesterol levels were higher in GHD. In GHD, ghrelin levels were significantly lower than in controls (193.9 +/- 27.1 vs. 298.1 +/- 32.5 pmol/l, respectively, P = 0.02), while ApN levels were similar (10.2 +/- 1.1 and 9 +/- 1 mg/l, respectively, P = ns). After 1 year of rhGH therapy, BF%, BMI, serum total and LDL cholesterol significantly decreased, serum leptin levels showed a trend to decrease, while HOMA-IR and QUICKI did not change. Ghrelin and ApN levels significantly increased from 193.9 +/- 27.1 to 232.4 +/- 26.3 pmol/l (P < 0.01) and from 8.6 +/- 0.8 to 10.3 +/- 1.1 mg/l (P < 0.05), respectively. In group B, the expected increase in IGF-I levels was associated with a significant decrease in ghrelin levels, while ApN did not change. CONCLUSION: GHD patients showed serum ghrelin lower than controls, probably due to the higher BF%. No difference in ApN was observed. Ghrelin and ApN increments induced by long-term treatment may be related to the significant BMI and BF% reduction that is the predominant metabolic effect of rhGH therapy. Conversely, the decrease in ghrelin levels observed after short-term rhGH administration may be consistent with an inhibitory feedback of GH and/or IGF-I on ghrelin release

Effects of modified sham feeding on ghrelin levels in healthy human subjects

Many hormonal and metabolic responses to nutrient intake begin during the cephalic or pre-absorptive phase and are mostly mediated by the autonomous nervous system. Ghrelin is a gut-brain hormone involved in the control of energy homeostasis with important orexigenic effects. The mechanisms involved in its preprandial rise and post-prandial fall are as yet unknown. The aim of the present study was to investigate the effects of the cephalic phase on ghrelin response to feeding in human subjects. The modified sham feeding (MSF), a well established technique in which nutrients are smelled, chewed, and tasted, but not swallowed, was used. Sixteen healthy volunteers were studied: 7 received a standardized mixed meal, and 9 underwent MSF. Several blood samples for ghrelin, insulin, glucose, PP were taken for 2h during both tests. Ghrelin levels significantly increased from -30 to 0 min before the 2 tests , then significantly decreased after both the real and the sham feeding, without significant differences being found by ANOVA. PP significantly increased also after MSF, while insulin and glucose levels were modified by the actual meal only. In conclusion, circulating ghrelin concentrations are decreased by sham feeding as they are by real feeding in humans. These findings underline the importance of the cephalic response to nutrient intake, and the role of vagal activity in the control of ghrelin secretion