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Reviews in Endocrine & Metabolic... Apr 2023Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal... (Review)
Review
Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.
Topics: Child; Humans; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Adrenal Glands
PubMed: 36763264
DOI: 10.1007/s11154-023-09784-7 -
Hormone Research in Paediatrics 2023The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the... (Review)
Review
BACKGROUND
The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the dose per square meter body surface area used in children of different ages and developmental phases have improved the situation and outcome for the patients. Neonatal screening enables an earlier diagnosis and initiation of treatment, prevents from adrenal crisis, and improves growth and development also for children with the less severe forms of CAH.
SUMMARY
This review describes the current treatment strategies for children with CAH and discusses some potential treatment options that have been developed with the primary aim to decrease the adrenal androgen production. Novel modified release glucocorticoid therapies are also discussed.
KEY MESSAGES
The long-term effects of the new adjunct therapies are unknown, and some are not suitable for use in children and adolescents. The effects of the new therapies on bone mineral density, gonadal functions, and long-term cognitive development are yet to be assessed. It is not known what levels of adrenal androgens are optimal for normal growth, puberty, and bone health. The basis of using glucocorticoids and mineralocorticoids in the treatment of CAH remains, and in some individuals, it may be beneficial to add therapies to reduce the androgen load during certain life stages.
Topics: Infant, Newborn; Adolescent; Child; Humans; Adrenal Hyperplasia, Congenital; Androgens; Glucocorticoids; Hydrocortisone; Mineralocorticoids
PubMed: 35086098
DOI: 10.1159/000522260 -
The Journal of Clinical Endocrinology... Aug 2023The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD), which in the classic (severe) form occurs in roughly 1:16 000 newborns... (Review)
Review
The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD), which in the classic (severe) form occurs in roughly 1:16 000 newborns worldwide. Lifelong treatment consists of replacing cortisol and aldosterone deficiencies, and supraphysiological dosing schedules are typically employed to simultaneously attenuate production of adrenal-derived androgens. Glucocorticoid titration in 21OHD is challenging as it must balance the consequences of androgen excess vs those from chronic high glucocorticoid exposure, which are further complicated by interindividual variability in cortisol kinetics and glucocorticoid sensitivity. Clinical assessment and biochemical parameters are both used to guide therapy, but the specific purpose and goals of each biomarker vary with age and clinical context. Here we review the approach to medication titration for children and adults with classic 21OHD, with an emphasis on how to interpret adrenal biomarker values in guiding this process. In parallel, we illustrate how an understanding of the pathophysiologic and pharmacologic principles can be used to avoid and to correct complications of this disease and consequences of its management using existing treatment options.
Topics: Child; Adult; Humans; Infant, Newborn; Adrenal Hyperplasia, Congenital; Glucocorticoids; Hydrocortisone; Steroids; Biomarkers; Disease Management; Steroid 21-Hydroxylase
PubMed: 36950738
DOI: 10.1210/clinem/dgad134 -
Frontiers in Endocrinology 2021Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and... (Review)
Review
Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.
Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Disorders of Sex Development; Humans; Sex Differentiation
PubMed: 34987475
DOI: 10.3389/fendo.2021.770782 -
Frontiers in Endocrinology 2022Since the introduction of glucocorticoid (GC) replacement therapy, congenital adrenal hyperplasia (CAH) is no longer a fatal disease. The development of neonatal... (Review)
Review
Since the introduction of glucocorticoid (GC) replacement therapy, congenital adrenal hyperplasia (CAH) is no longer a fatal disease. The development of neonatal screening programs and the amelioration of GC treatment strategies have improved significantly life expectancy in CAH patients. Thanks to these achievements, CAH patients are now in their adulthood, but an increased incidence of cardiovascular risk factors has been reported compared to general population in this stage of life. The aim of CAH treatment is to both prevent adrenal insufficiency and suppress androgen excess; in this delicate balance, under- as well as overtreatment might be equally harmful to long-term cardiovascular health. This work examines the prevalence of metabolic features and cardiovascular events, their correlation with hormone levels and GC replacement regimen in CAH patients and focuses on precocious markers to early detect patients at higher risk and new potential treatment approaches.
Topics: Adrenal Hyperplasia, Congenital; Adult; Cardiovascular Diseases; Glucocorticoids; Hormone Replacement Therapy; Humans; Infant, Newborn; Metabolic Syndrome
PubMed: 35979433
DOI: 10.3389/fendo.2022.934675 -
Endocrinology and Metabolism Clinics of... Jun 2016Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is a monogenic disorder of adrenal steroidogenesis. To prevent genital ambiguity, in girls,... (Review)
Review
Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is a monogenic disorder of adrenal steroidogenesis. To prevent genital ambiguity, in girls, prenatal dexamethasone treatment is administered early in the first trimester. Prenatal genetic diagnosis of CAH and fetal sex determination identify affected female fetuses at risk for genital virilization. Advancements in prenatal diagnosis are owing to improved understanding of the genetic basis of CAH and improved technology. Cloning of the CYP21A2 gene ushered in molecular genetic analysis as the current standard of care. Noninvasive prenatal diagnosis allows for targeted treatment and avoids unnecessary treatment of males and unaffected females.
Topics: Adrenal Hyperplasia, Congenital; Dexamethasone; Disorders of Sex Development; Female; Humans; Male; Pregnancy; Prenatal Diagnosis
PubMed: 27241964
DOI: 10.1016/j.ecl.2016.01.001 -
Physiological Research Sep 2020The adrenal glands produce significant amounts of steroid hormones and their metabolites, with various levels of androgenic activities. Until recently, the androgenic... (Review)
Review
The adrenal glands produce significant amounts of steroid hormones and their metabolites, with various levels of androgenic activities. Until recently, the androgenic potency of these adrenal-derived compounds were not well known, but some recent studies have shown that the production of 11-oxo- and 11beta-hydroxy-derived testosterone and dihydrotestosterone evidently have high androgenic activity. This fact has clinical importance, for instance, in various types of congenital adrenal hyperplasia with androgenization or polycystic ovarian syndrome, and laboratory determinations of these substances could help to better evaluate the total androgen pressure in patients with these disorders. Another area of concern is the treatment of prostate cancer with androgen deprivation, which loses effectiveness after a certain time. The concurrent blocking of the secretion of adrenal C(19)-steroids, whether using corticoids or adrenostatics, could increase the effectiveness of androgen-deprivation therapy.
Topics: Adrenal Hyperplasia, Congenital; Androgen Antagonists; Androgens; Animals; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Testosterone
PubMed: 33094617
DOI: 10.33549/physiolres.934516 -
Current Opinion in Endocrinology,... Jun 2021The introduction of synthetic glucocorticoids 70 years ago made survival possible in classic 21-hydroxylase deficiency (21OHD). The currently used glucocorticoid... (Review)
Review
PURPOSE OF REVIEW
The introduction of synthetic glucocorticoids 70 years ago made survival possible in classic 21-hydroxylase deficiency (21OHD). The currently used glucocorticoid therapy may lead to unphysiological dosing with negative consequencies on health in addition to the problems that may arise due to androgen over-exposure.
RECENT FINDINGS
Fertility in females with 21OHD seemed to be impaired, especially in the salt-wasting (SW) phenotype but when pregnancies did occur there was a higher risk for gestational diabetes and cesearean section. Increased fat mass, body mass index, insulin resistance and frequency of autoimmune disorders as well as impaired echocardiographic parameters and lower bone mineral density were found in 21OHD compared to controls. Negative effects on cognitive functions have been identified. Adrenal tumors, especially myelolipomas, were prevalent. Increased knowledge on steroid metabolism in 21OHD and urine steroid profiling may improve assessment of treatment efficacy. Nevanimibe, abiraterone acetate and anastrozole may have a place in the future management of 21OHD. Long-acting glucocorticoids may be a less favorable, especially dexamethasone.
SUMMARY
The various clinical outcomes need regular monitoring. Negative consequencies are to large extent the result of the unphysiological glucocorticoid replacement. Modern management with improved follow-up and future addition of new drugs may improve outcomes.
Topics: Adrenal Hyperplasia, Congenital; Female; Glucocorticoids; Humans
PubMed: 33741777
DOI: 10.1097/MED.0000000000000625 -
Journal of Clinical Research in... Nov 2023Patients with congenital adrenal hyperplasia (CAH) require lifelong therapy with glucocorticoids to suppress androgen excess and substitute for deficient cortisol. An... (Observational Study)
Observational Study
OBJECTIVE
Patients with congenital adrenal hyperplasia (CAH) require lifelong therapy with glucocorticoids to suppress androgen excess and substitute for deficient cortisol. An important aspect of care is the prevention of metabolic sequelae. In infants, potentially lethal nocturnal hypoglycaemia has been described. In adolescence, visceral obesity, hypertension, hyperinsulinism and insulin resistance are reported. To date, systematic studies of glucose profiles in this age group with CAH are lacking.
METHODS
This was a monocentric, prospective, observational study to determine the glucose profiles under different treatment regimens in a cohort of young patients with CAH. The continuous glucose monitoring device used was the latest generation FreeStyle Libre 3 sensor in blinded mode. Therapeutic and auxological data were obtained.
RESULTS
The cohort consisted of 10 children/adolescents with a mean age of 11 years. Three patients exhibited morning fasting hyperglycaemia. Overall, 6 out of 10 patients had unacceptably few total values in the desired range of 70-120 mg/dL. Tissue glucose values above 140-180 mg/dL were found in 5 of 10 patients. The mean value for glycosylated haemoglobin for the cohort was of 5.8%. All pubertal adolescents with reverse circadian regimens had significantly higher glucose levels at night. Two adolescents showed asymptomatic nocturnal hypoglycaemia.
CONCLUSION
Most of the patients exhibited abnormalities in glucose metabolism. Two-thirds had elevated total 24h glucose values outside the age-appropriate reference values. Thus, this aspect may need to be addressed early in life by adjusting the doses, treatment regimen or dietary measures. Consequently, reverse circadian therapy regimens should be critically indicated and closely monitored due to the potential metabolic risk.
Topics: Infant; Humans; Child; Adolescent; Adrenal Hyperplasia, Congenital; Blood Glucose; Prospective Studies; Blood Glucose Self-Monitoring; Hydrocortisone; Hypoglycemia; Glucose
PubMed: 37218136
DOI: 10.4274/jcrpe.galenos.2023.2023-3-5 -
Fertility and Sterility Jan 2019Couples at risk for autosomal recessive congenital adrenal hyperplasia often request anticipatory guidance and genetic counseling. Initially, hormones in amniotic fluid... (Review)
Review
Couples at risk for autosomal recessive congenital adrenal hyperplasia often request anticipatory guidance and genetic counseling. Initially, hormones in amniotic fluid were measured to distinguish affected female fetuses from unaffected fetuses. With the molecular era, more-targeted approaches became possible. Prenatal genetic diagnosis via amniocentesis or chorionic villus sampling was used to determine the need for continuing fetal therapy (dexamethasone), allowing cessation if the fetus was unaffected. Newer methods now allow diagnosis earlier in gestation, further shortening the treatment time for unaffected female fetuses who will not develop genital ambiguity. Preimplantation genetic testing permits transfer only of an unaffected female or male fetus. Analysis of maternal cell-free DNA based on quantitative differences in the amount of allele parental DNA permits affected pregnancies to be differentiated from unaffected pregnancies.
Topics: Adrenal Hyperplasia, Congenital; Embryo Transfer; Female; Genetic Counseling; Genetic Testing; Humans; Male; Pregnancy; Preimplantation Diagnosis; Prenatal Diagnosis
PubMed: 30611408
DOI: 10.1016/j.fertnstert.2018.11.041