3β-Hydroxysteroid dehydrogenaseJun 16, Author: In severely affected individuals, decreased mineralocorticoid secretion results in winstrol pct needed degrees of salt wasting in 3beta-hydroxysteroid dehydrogenase males and females, and deficient androgen production results 3beta-hydroxysteroid dehydrogenase ambiguous 3beta-hydroxysteroid dehydrogenase in 46,XY males. Hydrocortisone or other glucocorticoid replacement therapy may be needed to suppress excess androgen production. Decreased mineralocorticoid secretion results in varying degrees of salt wasting in both males and females, and deficient androgen production results in ambiguous genitalia in 46,XY males. Much heterogeneity is observed in the clinical presentation of this disorder.
3-Beta-Hydroxysteroid Dehydrogenase Deficiency: Practice Essentials, Background, Pathophysiology
Jun 16, Author: In severely affected individuals, decreased mineralocorticoid secretion results in varying degrees of salt wasting in both males and females, and deficient androgen production results in ambiguous genitalia in 46,XY males. Hydrocortisone or other glucocorticoid replacement therapy may be needed to suppress excess androgen production. Decreased mineralocorticoid secretion results in varying degrees of salt wasting in both males and females, and deficient androgen production results in ambiguous genitalia in 46,XY males.
Much heterogeneity is observed in the clinical presentation of this disorder. Although first described in male infants with ambiguous genitalia and severe salt wasting, 3-beta—hydroxysteroid dehydrogenase deficiency also occurs in 46,XX female infants who may have mild clitoromegaly , as well as in older patients who present with a milder or so-called late-onset variant. Anatomically, the adrenal gland can be divided into 3 zones, 1 the zona glomerulosa, which predominately produces mineralocorticoid, 2 the zona fasciculata, which predominately produces glucocorticoid, and 3 the zona reticularis, which predominantly produces androgens.
Think of the zona glomerulosa and the zonae fasciculata and reticularis as 2 separate endocrine organs because they are under separate control. Aldosterone mineralocorticoid synthesis and secretion is regulated via the renin-angiotensin system, which is responsive to the state of electrolyte balance and the plasma volume.
Aldosterone secretion is also directly stimulated by high serum potassium concentrations. By contrast, cortisol synthesis and secretion is regulated by adrenocorticotropic hormone ACTH , which stimulates the enzyme Pscc 20,22 desmolase , with subsequent increased production of all adrenal steroids in both the zona fasciculata and the zona reticularis see image below.
Congenital adrenal hyperplasia CAH is a family of autosomal recessive disorders of adrenal steroid biosynthesis [ 2 ] in which activity of one of the enzymes necessary for cortisol production is deficient see image below.
Decreased serum cortisol levels stimulate ACTH release via negative feedback. Increased ACTH secretion also produces overproduction of both the adrenal steroids preceding the missing enzyme and those not requiring the missing enzyme ie, build-up of compounds both before the block and "sideways" from the block.
Treatment with exogenous glucocorticoid results in decreased ACTH secretion and subsequent suppression of the overproduced steroids. An 8-kilobase kb gene, HSD3B2 , located on the p region of chromosome 1 encodes 3-beta—hydroxysteroid dehydrogenase. Type I 3-beta—hydroxysteroid dehydrogenase isoenzyme occurs in the peripheral tissues, primarily the liver.
Deficiencies of this isoenzyme primarily effect bile acid metabolism and may present with cholestasis, hepatomegaly, steatorrhea, failure to thrive, and low serum levels of the fat soluble vitamins A, E, and D. Type II 3-beta—hydroxysteroid dehydrogenase occurs almost exclusively in the gonads and adrenal glands [ 5 ] and is the focus of this review. Various mutations in the HSD3B2 gene have been shown to be responsible for the varying phenotypic presentations.
Patients with classic 3-beta—hydroxysteroid dehydrogenase deficiency have various nonconservative missense, nonsense, splicing, and frameshift mutations in the type II 3-beta—hydroxysteroid dehydrogenase gene with no mutation in the type I gene. Such mutations of the type II isoenzyme typically occur in gene domains essential for normal enzyme activity, but in vitro enzyme activity does not necessarily correlate with genital phenotype. Missense mutations in the type II gene have been described in nonclassic late-onset 3-beta—hydroxysteroid dehydrogenase deficiency.
The synthesis of all 3 groups of adrenal steroids requires 3-beta—hydroxysteroid dehydrogenase. The adrenal steroids are mineralocorticoids, glucocorticoids, and sex steroids. Therefore, absence of this enzyme impairs all steroid production. Low levels of cortisol result in increased ACTH stimulation of steroids prior to the 3-beta—hydroxysteroid dehydrogenase step, producing increased accumulation and secretion of pregnenolone, alpha-hydroxypregnenolone, and DHEA.
Adrenal insufficiency occurs secondary to aldosterone and cortisol deficiency. Reduced sex steroid production leads to ambiguous external genitalia in 46,XY individuals; some virilization may occur in 46,XX infants or in older children of either sex because of excessive DHEA production.
Affected 46,XX infants appear normal or may have mild-to-moderate clitoromegaly due to either direct androgen effects of elevated DHEA or peripheral conversion of excess DHEA to testosterone via peripheral type I 3-beta—hydroxysteroid dehydrogenase isoenzyme.
Effects of excessive androgen activity in older 46,XX children include acne , premature pubarche, and advanced linear and skeletal growth. By contrast, 46,XY infants present with varying degrees of ambiguous genitalia due to defective androgen production. Virilization or spontaneous puberty has been reported in occasional male patients secondary to either direct effects of DHEA or to sufficient conversion of DHEA to testosterone via peripheral type I 3-beta—hydroxysteroid dehydrogenase isoenzyme.
Finally, a deficiency in the related 3-alpha-hydrozysteroid dehydrogenase may also play a role in hirsutism. The incidence of classic hydroxylase deficiency varies by population and ranges from 1 case per , live births to as high as 1 case per births in Alaskan Yupik Eskimos. The next most common type of CAH, beta-hydroxylase deficiency, has an incidence of about 1 in , persons. In one study of 81 children with ambiguous genitalia, only 2 were found to have 3-beta—hydroxysteroid dehydrogenase deficiency.
Mild 3-beta—hydroxysteroid dehydrogenase defects are probably rare because most children with premature appearance of pubic hair pubarche or older women with irregular menstrual cycles and hirsutism and mildly elevated DHEA or hydroxypregnenolone levels only rarely have mutations in the 3-beta—hydroxysteroid dehydrogenase II gene.
For example, in , Sakkal-Alkaddour et al reported normal type II 3-beta—hydroxysteroid dehydrogenase gene sequences in 15 infants and children with premature pubarche and mildly elevated DHEA levels. Therefore, absence of this enzyme impairs all steroid production, and adrenal insufficiency occurs secondary to aldosterone and cortisol deficiency.
A great deal of heterogeneity is observed with 3-beta—hydroxysteroid dehydrogenase deficiency. The most severely affected patients may have fatal salt-losing adrenal crises in infancy. By contrast, some patients with classic 3-beta—hydroxysteroid dehydrogenase deficiency do not have salt-losing crises; milder or late-onset variants have also been described in which patients do not present until later childhood or adolescence.
Prognosis is usually good-to-excellent with adequate replacement glucocorticoid and mineralocorticoid if needed therapy and monitoring. Sex steroid replacement may be necessary for the development of secondary sexual characteristics in both males and females and cyclic menstrual bleeding in females. Patients with complete 3-beta—hydroxysteroid dehydrogenase deficiency are at risk for acute adrenal insufficiency when ill. If medication can be taken orally, the patient should double or triple the usual dose of glucocorticoid for 3 days.
Mineralocorticoid doses do not need to be increased. If the patient cannot take the medication orally because of vomiting, altered state of consciousness, or surgery, parenteral glucocorticoids, preferably hydrocortisone, should be administered.
Patients should wear MedicAlert identification and be taken to their local health care provider as soon as possible when acutely ill for evaluation. Disorders of sex differentiation. Williams Textbook of Endocrinology. WB Saunders Co; Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. New insight into the molecular basis of 3beta-hydroxysteroid dehydrogenase deficiency: J Clin Endocrinol Metab. Variable clinical spectrum of the most common inborn error of bile acid metabolismbeta-hydroxy-Delta 5-Csteroid dehydrogenase deficiency.
J Pediatr Gastroenterol Nutr. Carboxyl-terminal mutations in 3beta-hydroxysteroid dehydrogenase type II cause severe salt-wasting congenital adrenal hyperplasia. Persistent testicular delta5-isomerase-3beta-hydroxysteroid dehydrogenase deltabeta-HSD deficiency in the deltabeta-HSD form of congenital adrenal hyperplasia. Studies of 3 beta-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated delta 5-steroid levels.
Delayed diagnosis of congenital adrenal hyperplasia with salt wasting due to type II 3beta-hydroxysteroid dehydrogenase deficiency. A case of 3beta-hydroxysteroid dehydrogenase type II HSD3B2 deficiency picked up by neonatal screening for hydroxylase deficiency: Jeandron DD, Sahakitrungruang T.
Detection and functional characterization of the novel missense mutation YD in type II 3 beta-hydroxysteroid dehydrogenase 3 beta HSD gene of a female patient with nonsalt-losing 3 beta HSD deficiency. Refining hormonal diagnosis of type II 3beta-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. Congenital adrenal hyperplasia due to steroid hydroxylase deficiency: Relationship between final height and health outcomes in adults with congenital adrenal hyperplasia: Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: Timing and type of glucocorticoid replacement in adult congenital adrenal hyperplasia.
Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to hydroxylase deficiency. Testicular adrenal rest tumors and Leydig and Sertoli cell function in boys with classical congenital adrenal hyperplasia. Sonography of congenital adrenal hyperplasia due to partial deficiency of 3beta-hydroxysteroid dehydrogenase: Prevalence of 3beta-hydroxysteroid dehydrogenase-deficient nonclassic adrenal hyperplasia in hyperandrogenic women with adrenal androgen excess.
Am J Obstet Gynecol. Structure-function relationships of 3 beta-hydroxysteroid dehydrogenase: Congenital adrenal hyperplasia due to point mutations in the type II 3 beta-hydroxysteroid dehydrogenase gene. The interrelationship of sodium balance, plasma renin activity and ACTH in congenital adrenal hyperplasia. American Association of Clinical Endocrinologists Disclosure: Sign Up It's Free! If you log out, you will be required to enter your username and password the next time you visit. Share Email Print Feedback Close.
Sections 3-Beta-Hydroxysteroid Dehydrogenase Deficiency. Practice Essentials 3-Beta—hydroxysteroid dehydrogenase 3BHSD deficiency is a rare form of congenital adrenal hyperplasia that results in decreased production of all 3 groups of adrenal steroids: Background 3-Beta—hydroxysteroid dehydrogenase 3BHSD deficiency is a rare genetic disorder of steroid biosynthesis that results in decreased production of all 3 groups of adrenal steroids, which include mineralocorticoids, glucocorticoids, and sex steroids.
Pathophysiology Anatomically, the adrenal gland can be divided into 3 zones, 1 the zona glomerulosa, which predominately produces mineralocorticoid, 2 the zona fasciculata, which predominately produces glucocorticoid, and 3 the zona reticularis, which predominantly produces androgens.
Normal adrenal steroid biosynthesis results in 3 products: Cortisol production is regulated by feedback with adrenocorticotropic hormone ACTH.
ACTH stimulates the enzyme Pscc 20,22 desmolase with subsequent increased production of all adrenal steroids. Representation of typical congenital adrenal hyperplasia CAH. In this example, both the mineralocorticoid and glucocorticoid pathways are deficient.
Decreased serum cortisol levels stimulate adrenocorticotropic hormone ACTH release via negative feedback. Increased ACTH secretion results in overproduction of adrenal steroids preceding the missing enzyme as well as those not requiring the missing enzyme. In this example, a deficiency of hydroxylase results in deficient mineralocorticoid and glucocorticoid production and excessive androgen production. Complete absence of this enzyme thus impairs all steroid production.
Prognosis 3-Beta—hydroxysteroid dehydrogenase is required for the synthesis of all 3 groups of adrenal steroids, which are mineralocorticoids, glucocorticoids, and sex steroids. Patient Education Patients with complete 3-beta—hydroxysteroid dehydrogenase deficiency are at risk for acute adrenal insufficiency when ill.
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