Chrisanthi Marakaki

Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension

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.

Negativation of type 1 diabetes-associated autoantibodies to glutamic acid decarboxylase and insulin in children treated with oral calcitriol.

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.

Negativation of type 1 diabetes-associated autoantibodies to glutamic acid decarboxylase and insulin in children treated with oral calcitriol (口服骨化三醇治疗维持儿童1型糖尿病相关的谷氨酸脱羧酶与胰岛素自身抗体阴性)

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.

Early Adiposity Rebound and Premature Adrenarche

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.

L-Dopa Is a Potent Stimulator of Cortisol in Short Children

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.

L-Dopa Stimulates Cortisol Secretion through Adrenocorticotropic Hormone Release in Short Children

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.

Increased symptoms of anxiety and depression in prepubertal girls, but not boys, with premature adrenarche: associations with serum DHEAS and daily salivary cortisol concentrations

Abstract 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.

A Greek girl with 11β-hydroxylase deficiency due to compound heterozygosity for two novel mutations in CYP11B1 gene

Summary 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 reported Regarding 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.

Improvement of HbA1c is blunted following discontinuation of an on-line telemonitoring system, in patients with inefficiently controlled insulin-treated diabetes mellitus

Aim IMPROVEMENT OF HbA1c IS BLUNTED FOLLOWING DISCONTINUATION OF AN ON-LINE TELEMONITORING SYSTEM, IN PATIENTS WITH INEFFICIENTLY CONTROLLED INSULIN-TREATED DIABETES MELLITUS. Stelios Fountoulakis, Labrini Papanastasiou, Dimosthenis Malliopoulos, Marakaki Chrisanthi, Athina Markou, Theodora Kounadi, George Piaditis. Department of Endocrinology and Diabetes Center, “G. Gennimatas” General Hospital of Athens, Athens, Greece.

Negativation of type 1 diabetes-associated autoantibodies to glutamic acid decarboxylase and insulin in children treated with oral calcitriol (口服骨化三醇治疗维持儿童1型糖尿病相关的谷氨酸脱羧酶与胰岛素自身抗体阴性): Calcitriol and type 1 diabetes

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.