Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11β-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal steroidogenesis. Patients with classic 21OHD and 11OHD have a (nearly) complete enzyme deficiency resulting in impaired cortisol synthesis. Elevated precursor steroids are shunted into the unaffected adrenal androgen synthesis pathway leading to elevated adrenal androgen concentrations in these patients. Classic patients are treated with glucocorticoid substitution to compensate for the low cortisol levels and to decrease elevated adrenal androgens levels via negative feedback on the pituitary gland. On the contrary, non-classic CAH (NCCAH) patients have more residual enzymatic activity and do generally not suffer from clinically relevant glucocorticoid deficiency. However, these patients may develop symptoms due to elevated adrenal androgen levels, which are most often less elevated compared to classic patients. Although glucocorticoid treatment can lower adrenal androgen production, the supraphysiological dosages also may have a negative impact on the cardiovascular system and bone health. Therefore, the benefit of glucocorticoid treatment is questionable. An individualized treatment plan is desirable as patients can present with various symptoms or may be asymptomatic. In this review, we discuss the advantages and disadvantages of different treatment options used in patients with NCCAH due to 21OHD and 11OHD.
Context Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice-daily, but there is debate about the optimal timing of highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). Objective We aimed to compare two standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure, sleep and activity scores. Design and setting Six-week cross-over study. Patients Thirty-nine patients (4-19 years) with 21OHD. Interventions Patients were treated for three weeks with highest hydrocortisone dose in the morning, followed by three weeks with highest dose in the evening (n=21), or vice-versa (n=18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5.00am; 7.00am; 3.00pm; and 11.00pm during the last two days of each treatment period. Main outcome measure Comparison of saliva 17OHP and A4 levels between two treatment strategies. Results Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5.00am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The two treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal blood pressure, and activity- and sleep scores. Conclusion No clear benefit for either treatment schedule was established. Given the variation in individual responses we recommend to individually optimize dose distribution and monitoring disease control at multiple timepoints.
Testicular Adrenal Rest Tumors (TART) are a common complication of unknown origin in patients with Congenital Adrenal Hyperplasia. These benign tumors may derive from cells of adrenal origin or from pluripotent progenitor cells from the fetal adrenogonadal primordium. By comparing the transcriptome of TART with fetal-and adulttestis and adrenal tissues, this study aims to unravel the origin of TART. Targeted transcriptome sequencing was followed by unsupervised clustering-, differential expression-, functional enrichment-and pathway analyses. Immunohistochemistry demonstrated co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART, indicating the existence of a distinct TART cell exhibiting both adrenal-and testicular characteristics. Principal component analysis indicated that the TART transcriptome was distinct from either adrenal or testis fetal tissue, making a progenitor-like phenotype of TART unlikely. Rather, TART appears to originate from -or differentiate into-a mature cell type, with both adrenal-and testicular characteristics. The present study, the first to describe the TART transcriptome, expands knowledge about the identity and functional characteristics of TART and identifies clinically targetable pathways associated with fibrosis.
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