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Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency. This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated. The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected. In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment.

Short stature in adulthood can be considered as a disability because it can be associated with many difficulties including those of a psychological and social nature. Many factors can influence final adult height such as genetics, the magnitude of growth hormone (GH) secretion, height before puberty, and the onset and duration of puberty. A crucial factor affecting final adult height, however, is the total height achieved during puberty. The combination of GH and gonadotropin-releasing hormone analogues greatly enhances growth and their separate and combined use for the treatment of GH deficiency, central precocious puberty and other diagnoses in children and adolescents is discussed in this article.

In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels and lowering glucocorticoid doses in pediatric participants with classic congenital adrenal hyperplasia.

In adults with congenital adrenal hyperplasia, crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, lowered the mean glucocorticoid dose and decreased the mean androstenedione level.

Abstract Background Prenatal treatment with dexamethasone (DEX) reduces virilization in girls with congenital adrenal hyperplasia (CAH). The treatment is effective but may result in long-lasting adverse effects. In this study we explore the effects of DEX on metabolism in individuals not having CAH but treated with DEX during the first trimester of fetal life. Method All DEX-treated participants (n = 40, age range 5.1-26.4 years) and controls (n = 75, age range 4.5-26.6 years) were assessed with fasting blood samples to measure blood count, renal function, glucose homeostasis, and serum lipid profiles. Results There were no significant differences between DEX and control participants for birth parameters, weight and height, or body mass index at the time of testing. Analyzing the entire cohort, we found no significant effects of DEX on blood count, renal function, or serum lipid profiles. However, a lower HOMA-β index in the DEX-treated individuals (U = 893.0; P = 0.049) was observed. Post hoc analyses revealed an effect in girls (U = 152.5; P = 0.024) but not in boys (U = 299.5; P = 0.550). The effect on HOMA-β persisted (U = 117.5; P = 0.048) after analyzing data separately in the participants < 16 years of age. In addition, we observed higher plasma glucose levels (F = 14.6; P = 0.001) in the DEX-treated group. The participants ≥ 16 years of age in the DEX-treated group had significantly higher total plasma cholesterol (F = 9.8; P = 0.003) and higher low-density lipoprotein cholesterol levels (F = 7.4; P = 0,009). Conclusion Prenatal DEX exposure in early pregnancy has negative effects on beta-cell function and lipid profile in individuals without CAH already at a young age.

21-Hydroxylase deficiency (21-OHD) is the most common cause of congenital adrenal hyperplasia (CAH), resulting from deletions or mutations of the P450 21-hydroxylase gene (CYP21A2). Children with 21-OHD need chronic glucocorticoid (cGC) therapy, both to replace congenital deficit in cortisol synthesis and to reduce androgen secretion by adrenal cortex. GC-induced osteoporosis (GIO) is the most common form of secondary osteoporosis that results in an early, transient increase in bone resorption accompanied by a decrease in bone formation, maintained for the duration of GC therapy. Despite the conflicting results in the literature about the bone status on GC-treated patients with 21-OHD, many reports consider these subjects to be at risk for osteoporosis and fractures. In bone cells, at the molecular level, GCs regulate various functions including osteoblastogenesis, osteoclastogenesis, and the apoptosis of osteoblasts and osteocytes. In this paper, we focus on the physiology and biosynthesis of endogenous steroid hormones as well as on the effects of GCs on bone cells, highlighting the pathogenetic mechanism of GIO in children with 21-OHD.

Abstract Context Prenatal treatment of human disease is rare. Dexamethasone (DEX) is used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in an affected female fetus. The safety and long-term consequences of prenatal DEX exposure on the brain are largely unknown. Objective We investigate whether first-trimester prenatal DEX treatment is associated with alterations in brain structure at adult age, and if these alterations are associated with DNA methylation, mood, and cognitive abilities. Design, Setting, and Participants T1-weighted and diffusion-weighted imaging scans, from a single research institute, are compared between 19 (9 women) first-trimester DEX-treated individuals, at risk of CAH but not having CAH, and 43 (26 women) controls (age range, 16.0-26.4 years). Results DEX-treated participants showed bilateral enlargement of the amygdala, increased surface area and volume of the left superior frontal gyrus, and widespread increased radial, mean, and axial diffusivity of white matter, in particular in the superior longitudinal fasciculi and corticospinal tracts. In the DEX-treated group, increased mean and radial diffusivity correlated with increased methylation of the promotor region of the FKBP5 gene. There were no group differences in cognition or in scales assessing depression or anxiety, and the relationship between brain structure and cognition did not differ between DEX-treated and controls. Conclusions First-trimester prenatal DEX treatment is associated with structural alterations of the brain at adult age, with an accompanying change in gene methylation. The findings add to the safety concerns of prenatal DEX treatment in the context of CAH.

Adrenal insufficiency (AI) in a newborn due to hypothalamic–pituitary–adrenal (HPA) axis suppression after maternal glucocorticoid therapy during pregnancy is a rare condition. We report an AI triggered by a nosocomial infection in a premature newborn. The suspected mechanism was the suppression of the HPA axis due to high doses of maternal glucocorticoid treatment during pregnancy. AI was revealed by recurrent hypoglycaemia and mild hyponatraemia during the neonatal period. His twin brother did not develop AI, showing the variable sensitivity of adrenal suppression after exposure to the same glucocorticoid dose. The affected boy was substituted with hydrocortisone until the age of 2 years. At this age, basal morning values for cortisol and Adrenocorticotropic hormone (ACTH) had normalised. The patient also suffers from galactosaemia. We suggest screening for AI, by testing for hypoglycaemia and hyponatraemia, in newborns who were exposed to high doses of maternal methylprednisolone treatment during the pregnancy and to include galactosaemia in national neonatal screening programmes.