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Endocrine Reviews Jan 2022Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol... (Review)
Review
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.
Topics: Adrenal Hyperplasia, Congenital; Humans; Hydrocortisone; Infant, Newborn; Mutation; Neonatal Screening; Steroid 21-Hydroxylase
PubMed: 33961029
DOI: 10.1210/endrev/bnab016 -
Journal of Pediatric and Adolescent... Oct 2017The congenital adrenal hyperplasias comprise a family of autosomal recessive disorders that disrupt adrenal steroidogenesis. The most common form is due to... (Review)
Review
The congenital adrenal hyperplasias comprise a family of autosomal recessive disorders that disrupt adrenal steroidogenesis. The most common form is due to 21-hydroxylase deficiency associated with mutations in the 21-hydroxylase gene, which is located at chromosome 6p21. The clinical features associated with each disorder of adrenal steroidogenesis represent a clinical spectrum that reflect the consequences of the specific mutations. Treatment goals include normal linear growth velocity and "on-time" puberty in affected children. For adolescent and adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and preservation of fertility. For adolescent and adult men, prevention and early treatment of testicular adrenal rest tumors is beneficial. In this article key aspects regarding pathophysiology, diagnosis, and treatment of congenital adrenal hyperplasia are reviewed.
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Child; Female; Fertility; Hirsutism; Humans; Male; Mutation; Sexual Maturation; Steroid 21-Hydroxylase
PubMed: 28450075
DOI: 10.1016/j.jpag.2017.04.001 -
Endocrinology and Metabolism Clinics of... Mar 2021Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases.... (Review)
Review
Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases. Non-classic 21-hydroxylase deficiency is due to partial enzymatic defects, which present with normal cortisol synthesis, but excessive production of adrenal androgens, including 11-oxygenated androgens. Non-classic 21-hydroxylase deficiency is relatively common, and its phenotype resembles closely that of polycystic ovary syndrome. This review focuses primarily on non-classic 21-hydroxylase deficiency, its clinical features, diagnosis, and management.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Endocrinologists; Female; Humans; Polycystic Ovary Syndrome
PubMed: 33518183
DOI: 10.1016/j.ecl.2020.10.008 -
Nature Reviews. Endocrinology Jun 2022Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although... (Review)
Review
Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although major advances in molecular biology have delineated steroidogenic mechanisms and the genetics of CAH, management and treatment of this condition continue to present challenges. Management is complicated by a combination of comorbidities that arise from disease-related hormonal derangements and treatment-related adverse effects. The clinical outcomes of CAH can include life-threatening adrenal crises, altered growth and early puberty, and adverse effects on metabolic, cardiovascular, bone and reproductive health. Standard-of-care glucocorticoid formulations fall short of replicating the circadian rhythm of cortisol and controlling efficient adrenocorticotrophic hormone-driven adrenal androgen production. Adrenal-derived 11-oxygenated androgens have emerged as potential new biomarkers for CAH, as traditional biomarkers are subject to variability and are not adrenal-specific, contributing to management challenges. Multiple alternative treatment approaches are being developed with the aim of tailoring therapy for improved patient outcomes. This Review focuses on challenges and advances in the management and treatment of CAH due to 21-hydroxylase deficiency, the most common type of CAH. Furthermore, we examine new therapeutic developments, including treatments designed to replace cortisol in a physiological manner and adjunct agents intended to control excess androgens and thereby enable reductions in glucocorticoid doses.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Biomarkers; Glucocorticoids; Humans; Hydrocortisone
PubMed: 35411073
DOI: 10.1038/s41574-022-00655-w -
The Journal of Clinical Endocrinology... Apr 2021Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes.
OBJECTIVE
We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control.
METHODS
A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study.
RESULTS
The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months' extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy).
CONCLUSION
MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.
Topics: Adrenal Hyperplasia, Congenital; Adult; Aged; Anti-Inflammatory Agents; Female; Follow-Up Studies; Humans; Hydrocortisone; Male; Middle Aged; Prognosis; Young Adult
PubMed: 33527139
DOI: 10.1210/clinem/dgab051 -
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 -
Acta Biochimica Polonica 2018The aim of this paper is a straightforward presentation of the steroidogenesis process and the most common type of congenital adrenal hyperplasia (CAH) - 21-hydroxylase... (Review)
Review
The aim of this paper is a straightforward presentation of the steroidogenesis process and the most common type of congenital adrenal hyperplasia (CAH) - 21-hydroxylase deficiency - as well as the analytical diagnostic methods that are used to recognize this disease. CAH is a family of common autosomal recessive disorders characterized by impaired adrenal cortisol biosynthesis with associated androgen excess due to a deficiency of one or more enzymes in the steroidogenesis process within the adrenal cortex. The most common and prototypical example of the CAH disorders group (90-95%) is caused by 21-hydroxylase deficiency. Less frequent types of CAH are 11β-hydroxylase deficiency (up to 8% of cases), 17α-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, P450 oxidoreductase deficiency and StAR deficiencies. In the 21-hydroxylase and 11β-hydroxylase deficiency, only adrenal steroidogenesis is affected, whereas a defect in 3β-hydroxysteroid dehydrogenase or 17α-hydroxylase also involves gonadal steroid biosynthesis. Many countries have introduced newborn screening programs based on immunoassays measuring 17-hydroxyprogesterone from blood spots used for other neonatal screening tests which enable faster diagnosis and treatment of CAH. Currently, chromatographic techniques coupled with mass spectrometry are gaining popularity due to an increase in the reliability of the test results.
Topics: Adrenal Hyperplasia, Congenital; Humans; Infant, Newborn; Neonatal Screening; Steroids
PubMed: 29543924
DOI: 10.18388/abp.2017_2343 -
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 -
Reviews in Endocrine & Metabolic... Feb 2023Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex, most commonly due to 21-hydroxylase deficiency... (Review)
Review
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex, most commonly due to 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene. Although women with CAH have decreased fecundity, they are able to conceive; thus, if pregnancy is not desired, contraception options should be offered. If fertility is desired, women with classic CAH should first optimize glucocorticoid treatment, followed by ovulation induction medications and gonadotropins if needed. Due to the possible pregnancy complications and implications on the offspring, preconception genetic testing and counseling with a high-risk obstetrics specialist is recommended. For couples trying to avoid having a child with CAH, care with a reproductive endocrinology and infertility specialist to utilize in vitro fertilization can be offered, with or without preimplantation genetic testing for monogenic disorders. Prenatal screening and diagnosis options during pregnancy include maternal serum cell free-DNA for sex of the baby, and chorionic villus sampling and amniocentesis for diagnosis of CAH. Pregnant women with classic CAH need glucocorticoids to be adjusted during the pregnancy, at the time of delivery, and postpartum, and should be monitored for adrenal crisis. Maternal and fetal risks may include chorioamnionitis, maternal hypertension, gestational diabetes, cesarean section, and small for gestational age infants. This review on CAH due to 21-hydroxylase deficiency highlights reproductive health including genetic transmission, contraception options, glucocorticoid management, fertility treatments, as well as testing, antenatal monitoring, and management during pregnancy, delivery, and postpartum.
Topics: Child; Pregnancy; Female; Humans; Adrenal Hyperplasia, Congenital; Glucocorticoids; Cesarean Section; Postpartum Period; Steroid 21-Hydroxylase
PubMed: 36399318
DOI: 10.1007/s11154-022-09770-5 -
The Journal of Clinical Endocrinology... Sep 2010We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH).
OBJECTIVE
We developed clinical practice guidelines for congenital adrenal hyperplasia (CAH).
PARTICIPANTS
The Task Force included a chair, selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), ten additional clinicians experienced in treating CAH, a methodologist, and a medical writer. Additional experts were also consulted. The authors received no corporate funding or remuneration.
CONSENSUS PROCESS
Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments.
CONCLUSIONS
We recommend universal newborn screening for severe steroid 21-hydroxylase deficiency followed by confirmatory tests. We recommend that prenatal treatment of CAH continue to be regarded as experimental. The diagnosis rests on clinical and hormonal data; genotyping is reserved for equivocal cases and genetic counseling. Glucocorticoid dosage should be minimized to avoid iatrogenic Cushing's syndrome. Mineralocorticoids and, in infants, supplemental sodium are recommended in classic CAH patients. We recommend against the routine use of experimental therapies to promote growth and delay puberty; we suggest patients avoid adrenalectomy. Surgical guidelines emphasize early single-stage genital repair for severely virilized girls, performed by experienced surgeons. Clinicians should consider patients' quality of life, consulting mental health professionals as appropriate. At the transition to adulthood, we recommend monitoring for potential complications of CAH. Finally, we recommend judicious use of medication during pregnancy and in symptomatic patients with nonclassic CAH.
Topics: Adrenal Hyperplasia, Congenital; Algorithms; Comorbidity; Evidence-Based Practice; Female; Humans; Infant, Newborn; Models, Biological; Neonatal Screening; Practice Guidelines as Topic; Pregnancy; Steroid 21-Hydroxylase
PubMed: 20823466
DOI: 10.1210/jc.2009-2631