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European Journal of Endocrinology Nov 2021Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility,... (Review)
Review
BACKGROUND
Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.
METHODS
Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.
SUMMARY
Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.
CONCLUSIONS
CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Circadian Rhythm; Endocrinology; Glucocorticoids; Hormone Replacement Therapy; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System
PubMed: 34735372
DOI: 10.1530/EJE-21-0794 -
Frontiers in Endocrinology 2022Congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase deficiency (21OHD) or 11β-hydroxylase deficiency (11OHD) are congenital conditions with affected adrenal... (Review)
Review
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 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.
Topics: Humans; Adrenal Hyperplasia, Congenital; Glucocorticoids; Hydrocortisone; Androgens; Mixed Function Oxygenases
PubMed: 36578966
DOI: 10.3389/fendo.2022.1064024 -
Human Mutation Jan 2018Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of adrenal steroidogenesis. Disorders in steroid 21-hydroxylation account for over 95%... (Review)
Review
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of adrenal steroidogenesis. Disorders in steroid 21-hydroxylation account for over 95% of patients with CAH. Clinically, the 21-hydroxylase deficiency has been classified in a broad spectrum of clinical forms, ranging from severe or classical, to mild late onset or non-classical. Known allelic variants in the disease causing CYP21A2 gene are spread among different sources. Until recently, most variants reported have been identified in the clinical setting, which presumably bias described variants to pathogenic ones, as those found in the CYPAlleles database. Nevertheless, a large number of variants are being described in massive genome projects, many of which are found in dbSNP, but lack functional implications and/or their phenotypic effect. In this work, we gathered a total of 1,340 GVs in the CYP21A2 gene, from which 899 variants were unique and 230 have an effect on human health, and compiled all this information in an integrated database. We also connected CYP21A2 sequence information to phenotypic effects for all available mutations, including double mutants in cis. Data compiled in the present work could help physicians in the genetic counseling of families affected with 21-hydroxylase deficiency.
Topics: Adrenal Hyperplasia, Congenital; Alleles; Databases, Genetic; Genetic Association Studies; Genetic Variation; Genotype; Humans; Mutation; Phenotype; Steroid 21-Hydroxylase
PubMed: 29035424
DOI: 10.1002/humu.23351 -
Indian Journal of Pediatrics Feb 2019
Review
Topics: Adrenal Hyperplasia, Congenital; Humans
PubMed: 30607772
DOI: 10.1007/s12098-018-2841-7 -
Frontiers in Endocrinology 2020
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Child; Female; Hirsutism; Humans; Male; Patient-Centered Care; Polycystic Ovary Syndrome; Prognosis; Treatment Outcome; Young Adult
PubMed: 32296393
DOI: 10.3389/fendo.2020.00170 -
Radiographics : a Review Publication of... 2021
Topics: Adrenal Hyperplasia, Congenital; Humans; Hyperplasia
PubMed: 34197246
DOI: 10.1148/rg.2021210118 -
Experientia Supplementum (2012) 2019Congenital adrenal hyperplasia (CAH) is a group of seven autosomal recessively inherited disorders of various enzymes participating in adrenal steroid hormone synthesis.... (Review)
Review
Congenital adrenal hyperplasia (CAH) is a group of seven autosomal recessively inherited disorders of various enzymes participating in adrenal steroid hormone synthesis. Patients present with various symptoms depending on the nature and severity of the enzymatic block. More than 95% of all CAH patients suffer from 21-hydroxylase deficiency. The genetic background is well characterized for all CAH subtypes. Characterization of their genetic background has provided important pathophysiologic understanding of steroid biosynthesis disorders. Genotyping is important for confirming diagnosis, determining prognostic factors, and for genetic counseling for family planning and may reveal new therapeutic approaches.
Topics: Adrenal Hyperplasia, Congenital; Genetic Background; Genetic Counseling; Humans
PubMed: 31588535
DOI: 10.1007/978-3-030-25905-1_12 -
Tidsskrift For Den Norske Laegeforening... Apr 2017Congenital adrenal hyperplasia is attributed to inherited enzyme defects in the adrenal cortex. The classical form results in reduced production of cortisol and... (Review)
Review
Congenital adrenal hyperplasia is attributed to inherited enzyme defects in the adrenal cortex. The classical form results in reduced production of cortisol and aldosterone, accompanied by an increase in production of adrenal cortical androgens. This causes virilisation in girls, adrenocortical failure and early puberty in both sexes. This article describes the genetics, clinical picture, diagnostics and treatment.
Topics: Adrenal Hyperplasia, Congenital; Female; Glucocorticoids; Humans; Male; Puberty, Precocious; Steroid 21-Hydroxylase; Virilism
PubMed: 28383228
DOI: 10.4045/tidsskr.16.0376 -
Reviews in Endocrine & Metabolic... Jun 2022Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) need life-long medical treatment to replace the lacking glucocorticoids and... (Review)
Review
Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) need life-long medical treatment to replace the lacking glucocorticoids and potentially lacking mineralocorticoids and to lower elevated adrenal androgens. Long-term complications are common, including gonadal dysfunction, infertility, and cardiovascular and metabolic co-morbidity with reduced quality of life. These complications can be attributed to the exposure of supraphysiological dosages of glucocorticoids and the longstanding exposure to elevated adrenal androgens. Development of novel therapies is necessary to address the chronic glucocorticoid overexposure, lack of circadian rhythm in glucocorticoid replacement, and inefficient glucocorticoid delivery with concomitant periods of hyperandrogenism. In this review we aim to give an overview about the current treatment regimens and its limitations and describe novel therapies especially evaluated for 21OHD patients.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Glucocorticoids; Hormone Replacement Therapy; Humans; Quality of Life
PubMed: 35199280
DOI: 10.1007/s11154-022-09717-w -
Endocrinology and Metabolism (Seoul,... Aug 2022A plethora of negative long-term outcomes have been associated with congenital adrenal hyperplasia (CAH). The causes are multiple and involve supra-physiological gluco-... (Review)
Review
A plethora of negative long-term outcomes have been associated with congenital adrenal hyperplasia (CAH). The causes are multiple and involve supra-physiological gluco- and mineralocorticoid replacement, excess adrenal androgens both intrauterine and postnatal, elevated steroid precursor and adrenocorticotropic hormone levels, living with a congenital condition as well as the proximity of the cytochrome P450 family 21 subfamily A member 2 (CYP21A2) gene to other genes. This review aims to discuss the different long-term outcomes of CAH.
Topics: Adrenal Hyperplasia, Congenital; Humans; Steroid 21-Hydroxylase
PubMed: 35799332
DOI: 10.3803/EnM.2022.1528