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Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.

Normal growth pattern variations [i.e., constitutional advancement and constitutional delay of growth and puberty (CAGP and CDGP)] are the mirror image of each other and are associated with early puberty (EP) and delayed puberty (DP), respectively. Differences between CAGP and CDGP relate not only to auxological characteristics (height, weight) but also to insulin-like growth factor-1 (IGF-1). IGF-1 levels in CAGP are above average whereas in CDGP they are below average, suggesting a role for IGF-1 in the induction of these growth patterns. Herein, we provide data suggesting that early activation of the growth hormone (GH)/IGF-1 axis induces the growth pattern of CAGP. Moreover, we suggest that IGF-1 is a decisive factor for the release of the gonadotropin-releasing hormone (GnRH) inhibition brake that occurs in prepuberty. It is therefore crucial for puberty onset., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Concerns over anxiety and depressive symptoms in children with premature adrenarche (PA) have been recently raised. However, to date, most relevant studies are on a small number of girls. In this cross-sectional study, 82 pre-pubertal children (66 girls and 16 boys) diagnosed with PA, were compared to 63 control children regarding their psychological characteristics and hypothalamic-pituitary-adrenal (HPA) axis function, as assessed by salivary cortisol measurement. Symptoms of anxiety and depression were assessed by child self-report (Spence Children's Anxiety Scale (SCAS) and Depression self-rating scale for Children (DSRS)) and parent-report (Child Behaviour Checklist (CBCL)) tests validated for the Greek population. Salivary cortisol levels were determined directly after awakening (approximately 7am) and evening (8pm) of the same day. Morning serum DHEAS levels were assessed in PA children. Girls with PA scored significantly higher on anxiety (p = .016) and depression (p =.039) scales than controls. No group differences were noted for parent reports and children's salivary cortisol concentrations. Boys with PA did not demonstrate significant differences in any of the aforementioned parameters. Our findings suggest that girls with PA may be at higher risk for reporting symptoms of anxiety and depression than their non-PA peers. HPA axis dysregulation in this population was not documented.

Objectives: To examine differences in the growth pattern and the age at adiposity rebound (AR) between children with premature adrenarche (PA) and their healthy peers (controls)., Study Design: In this cross-sectional study of 82 prepubertal children with PA and 63 controls, the main outcome measures were height and body mass index SDS progression, from birth to presentation at the clinic, baseline biochemical and hormonal evaluation, bone age determination, and age at AR., Results: Children with PA were significantly taller and more adipose than controls from the first years of life. 33% of children with PA presented the growth pattern of constitutional advancement of growth (ie, early growth acceleration) vs 19% of controls (P = .045). Children with PA had an earlier AR compared with controls; mean age at AR in girls with PA was 3.73 (1.03) years vs 4.93 (1.36) years for control girls (P = .001) and in boys with PA was 3.45 (0.73) vs 5.10 (1.50) years in control boys (P = .048). Both obese and nonobese girls with PA were taller and had earlier age at AR compared with nonobese controls., Conclusions: Early AR and constitutional advancement of growth may be triggering factors for adrenal androgen production and PA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Context: Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA)., Objective: We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT)., Patients and Methods: One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs., Results: Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group., Conclusions: A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

Background/aims: We recently showed that L-Dopa administration is a potent stimulator of cortisol secretion in children with short stature. Herein, we examined whether adrenocorticotropic hormone (ACTH) is implicated in the mechanism by which cortisol is stimulated during the L-Dopa test., Methods: Nineteen children with short stature who fulfilled the auxological criteria for growth hormone (GH) deficiency and had a subnormal GH response to glucagon stimulation underwent a second GH stimulation test (L-Dopa test). Serum GH, cortisol and plasma ACTH were determined at baseline and every 30 min up to 120 min after oral L-Dopa administration. Peak values of GH >10 ng/ml, cortisol >18 μg/dl and ACTH >52 pg/ml were considered as normal response., Results: Normal response rates were 10.5% (2/19) for GH, 94.7% (18/19) for cortisol and 68.4% (13/19) for ACTH. Among the children with a normal response in ACTH, its concentration increased from a basal value (mean ± standard deviation) of 23.3 ± 9.6 to 290.3 ± 221 pg/ml, almost always 90-120 min after L-Dopa administration. Mean peak cortisol was 36.2 ± 9.1 μg/dl, and it peaked almost simultaneously with ACTH., Conclusion: Our data suggest a stimulatory effect of the dopaminergic system on the hypothalamic-pituitary-adrenal axis., (© 2015 S. Karger AG, Basel.)

Unlabelled: 11β-hydroxylase deficiency (11β-OHD), an autosomal recessive inherited disorder, accounts for 5-8% of congenital adrenal hyperplasia. In Greece, no cases of 11β-OHD have been described so far. The patient presented at the age of 13 months with mild virilization of external genitalia and pubic hair development since the age of 3 months. Hormonal profile showed elevated 11-deoxycortisol, adrenal androgens and ACTH levels. ACTH stimulation test was compatible with 11β-OHD. DNA of the proband and her parents was isolated and genotyped for CYP11B1 gene coding cytochrome P450c11. The girl was found to be compound heterozygous for two CYP11B1 novel mutations, p.Ala386Glu (exon 7), inherited from the father and p.Leu471Argin (exon 9) from the mother. Hydrocortisone supplementation therapy was initiated. Four years after presentation she remains normotensive, her growth pattern is normal and the bone age remains advanced despite adequate suppression of adrenal androgens., Learning Points: 11β-hydroxylase (CYP11B1) deficiency (11OHD; OMIM +202010) is the second most common cause of CAH accounting for approximately 5-8% of cases with an incidence of 1:100 000-1:200 000 live births in non-consanguineous populations.Two CYP11B1 inactivating novel mutations, p.Ala386Glu and p.Leu471Arg are reportedRegarding newborn females, in utero androgen excess results in ambiguous genitalia, whereas in the male newborn diagnosis may go undetected. In infancy and childhood adrenal androgen overproduction results in peripheral precocious puberty in boys and various degrees of virilization in girls.Accumulation of 11-deoxycorticosterone and its metabolites causes hypertension in about two thirds of patients.Diagnosis lies upon elevated 11-deoxycortisol and DOC plus upstream precursors, such as 17α-hydroxyprogesterone and Δ4-androstenedione.The established treatment of steroid 11β-OHD is similar to that of steroid 21-hydroxylase deficiency and consists of glucocorticoid administration in order to reduce ACTH-driven DOC overproduction resulting in hypertension remission and improvement of the virilization symptoms.

Aims: In this study, we evaluated the diagnostic usefulness of oral L-dopa as a stimulatory agent for cortisol., Methods: In 27 short children that were evaluated for possible growth hormone deficiency (GHD), the levels of serum GH and cortisol were determined after oral L-dopa administration and after i.m. glucagon administration. We defined cortisol concentrations >18 μg/dl (496 nmol/l) as adequate response. Peak GH concentration <10 ng/ml in both tests defined GHD., Results: Twenty-five out of the 27 children (93%) studied showed a normal cortisol response, i.e. a peak serum cortisol >18 μg/dl in the L-dopa test, whereas 19 children (70%) had a normal cortisol response after stimulation with glucagon. In the children with normal cortisol response in both tests, the mean peak serum cortisol concentration was 28.7 (SD 1.59) after L-dopa and 26.65 (SD 1.26) μg/dl after glucagon administration. There was no statistically significant difference in peak serum cortisol response to L-dopa between GH-deficient and GH-sufficient children [25.90 (SD 4.9) vs. 29.87 (SD 9.9) μg/dl, respectively]., Conclusions: These results clearly suggest that L-dopa administration is a potent stimulus for cortisol secretion at least in short children., (© 2014 S. Karger AG, Basel.)

Background: Based on recent knowledge of the possible involvement of 1,25-dihydroxyvitamin D in the pathogenesis of type 1 diabetes (T1D) and the results of its administration in animal models, we conducted a clinical trial by treating high-risk children, positive for T1D autoantibodies, with oral calcitriol., Methods: The present prospective trial was performed on 12 children (1.5-13 years old) who were investigated for the potential risk of T1D because of an already diagnosed association of celiac disease and autoimmune thyroiditis (four girls), autoimmune thyroiditis at a very young age (two girls, two boys), a diagnosis of T1D in siblings (two boys), and impaired glucose tolerance (IGT; one boy, one girl). Serum autoantibody levels, including islet cell autoantibodies, anti-glutamic acid decarboxylase (GAD) 65, insulin autoantibodies (IAA), and anti-tyrosine phosphatase, and markers of calcium metabolism were evaluated prior to and at 6-monthly intervals after the initiation of 0.25 μg/day calcitriol for 1-3 years., Results: In all children, persistent negativation of the anti-GAD65 antibodies and IAA was observed within 0.4-2.1 years. Of the two children with IGT, the boy proved to have maturity onset diabetes of the young (MODY) 2, whereas the glycemic profile was normalized in the girl., Conclusions: Despite the small number of subjects and the absence of a control group in the present study, 0.25 μg/day calcitriol effectively negativates anti-GAD65 antibodies and IAA after a median time of 6 months. This simple, safe, and low-cost strategy may prove effective in the prevention of T1D in the future., (© 2013 Wiley Publishing Asia Pty Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.)

Background: Subclinical Cushing syndrome in patients with adrenal incidentalomas has been associated with an increased prevalence of the metabolic syndrome and cardiovascular risk. The management of these patients, be it conservative or surgical, is still debated, but there is accumulating evidence that surgery is best and that laparoscopic adrenalectomy, when possible, is the most preferred procedure. Here we present the short- and long-term results of laparoscopic adrenalectomy for subclinical Cushing syndrome and determine the effect of this procedure on components of the metabolic syndrome., Methods: Twenty-nine patients, 8 men and 21 women with adrenal incidentalomas and subclinical Cushing syndrome who underwent laparoscopic adrenalectomy, were studied retrospectively. They had undergone postoperative follow-up for improvement or worsening of their arterial blood pressure, body weight, and fasting glucose level for a mean period of 77 months., Results: Preoperatively, 17 patients (58.6 %) had arterial hypertension, 14 (48.3 %) had a body mass index exceeding 27 kg/m(2), and 12 (41.4 %) had diabetes mellitus. Postoperatively, a decrease in mean arterial pressure was found in 12 patients (70.6 %), a decrease in body mass index in 6 patients (42.9 %), and an improvement in glycemic control in 5 patients (41.7 %)., Conclusions: Laparoscopic adrenalectomy is beneficial in many patients with subclinical Cushing syndrome because it reduces arterial blood pressure, body weight, and fasting glucose levels. Prospective randomized studies are needed to compare laparoscopic adrenalectomy with a conservative approach and to confirm these results.

Sodium iodide symporter (NIS) is a transmembrane glucoprotein located in the basolateral membrane of the follicular thyroid cells, as well as in other normal and abnormal tissues such as the lactating mammary gland, well differentiated thyroid carcinoma and breast adenocarcinoma. It uses the electrochemical gradient generated by the Na-K ATPase to import an iodide molecule to the intracellular space along with two sodium molecules. The importance of NIS to diagnostic and research activities of Nuclear Medicine such as the radioiodine uptake, serum levels of TSH, TPO and TBG and thyroid diseases, especially cancer are described. NIS gene cloning in 1996 opened new prospective in diagnosis and treatment of thyroid and other diseases.