scholarly journals MECHANISMS IN ENDOCRINOLOGY: Rare defects in adrenal steroidogenesis

2018 ◽  
Vol 179 (3) ◽  
pp. R125-R141 ◽  
Author(s):  
Walter L Miller
Keyword(s):  
Genetic Disorders ◽  
Regulatory Protein ◽  
Hydroxylase Deficiency ◽  
Rare Mutations ◽  
Chain Cleavage ◽  
Adrenal Steroidogenesis ◽  
Cleavage Enzyme ◽  
Different Populations ◽  
Steroidogenic Acute Regulatory ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders of adrenal steroidogenesis that impair cortisol synthesis, with compensatory increases in ACTH leading to hyperplastic adrenals. The term ‘CAH’ is generally used to mean ‘steroid 21-hydroxylase deficiency’ (21OHD) as 21OHD accounts for about 95% of CAH in most populations; the incidences of the rare forms of CAH vary with ethnicity and geography. These forms of CAH are easily understood on the basis of the biochemistry of steroidogenesis. Defects in the steroidogenic acute regulatory protein, StAR, disrupt all steroidogenesis and are the second-most common form of CAH in Japan and Korea; very rare defects in the cholesterol side-chain cleavage enzyme, P450scc, are clinically indistinguishable from StAR defects. Defects in 3β-hydroxysteroid dehydrogenase, which also causes disordered sexual development, were once thought to be fairly common, but genetic analyses show that steroid measurements are generally unreliable for this disorder. Defects in 17-hydroxylase/17,20-lyase ablate synthesis of sex steroids and also cause mineralocorticoid hypertension; these are common in Brazil and in China. Isolated 17,20-lyase deficiency can be caused by rare mutations in at least three different proteins. P450 oxidoreductase (POR) is a co-factor used by 21-hydroxylase, 17-hydroxylase/17,20-lyase and aromatase; various POR defects, found in different populations, affect these enzymes differently. 11-Hydroxylase deficiency is the second-most common form of CAH in European populations but the retention of aldosterone synthesis distinguishes it from 21OHD. Aldosterone synthase deficiency is a rare salt-losing disorder. Mild, ‘non-classic’ defects in all of these factors have been described. Both the severe and non-classic disorders can be treated if recognized.

scholarly journals Congenital Adrenal Hyperplasias Presenting in the Newborn and Young Infant

2020 ◽  
Vol 8 ◽  
Author(s):  
Antonio Balsamo ◽  
Federico Baronio ◽  
Rita Ortolano ◽  
Soara Menabo ◽  
Lilia Baldazzi ◽  
...  
Keyword(s):  
Screening Program ◽  
Young Infant ◽  
Regulatory Protein ◽  
Dried Blood Spots ◽  
Hydroxylase Deficiency ◽  
Chain Cleavage ◽  
Precise Diagnosis ◽  
Steroid Profiles ◽  
Steroidogenic Acute Regulatory ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia includes autosomal recessive conditions that affect the adrenal cortex steroidogenic enzymes (cholesterol side-chain cleavage enzyme; 3β-hydroxysteroid dehydrogenase; 17α-hydroxylase/17,20 lyase; P450 oxidoreductase; 21-hydroxylase; and 11β-hydroxylase) and proteins (steroidogenic acute regulatory protein). These are located within the three major pathways of the steroidogenic apparatus involved in the production of mineralocorticoids, glucocorticoids, and androgens. Many countries have introduced newborn screening program (NSP) based on 17-OH-progesterone (17-OHP) immunoassays on dried blood spots, which enable faster diagnosis and treatment of the most severe forms of 21-hydroxylase deficiency (21-OHD). However, in several others, the use of this diagnostic tool has not yet been implemented and clinical diagnosis remains challenging, especially for males. Furthermore, less severe classic forms of 21-OHD and other rarer types of CAHs are not identified by NSP. The aim of this mini review is to highlight both the main clinical characteristics and therapeutic options of these conditions, which may be useful for a differential diagnosis in the neonatal period, while contributing to the biochemical evolution taking place in the steroidogenic field. Currently, chromatographic techniques coupled with tandem mass spectrometry are gaining attention due to an increase in the reliability of the test results of NPS for detecting 21-OHD. Furthermore, the possibility of identifying CAH patients that are not affected by 21-OHD but presenting elevated levels of 17-OHP by NSP and the opportunity to include the recently investigated 11-oxygenated androgens in the steroid profiles are promising tools for a more precise diagnosis and monitoring of some of these conditions.

scholarly journals Spontaneous Feminization in a 46,XX Female Patient with Congenital Lipoid Adrenal Hyperplasia Due to a Homozygous Frameshift Mutation in the Steroidogenic Acute Regulatory Protein*

1997 ◽  
Vol 82 (5) ◽  
pp. 1511-1515 ◽  
Author(s):  
Himangshu S. Bose ◽  
Ora Hirsch Pescovitz ◽  
Walter L. Miller
Keyword(s):  
Frameshift Mutation ◽  
Regulatory Protein ◽  
Severe Form ◽  
Adrenal Hyperplasia ◽  
Hormone Production ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Low Levels ◽  
Steroidogenic Cells ◽  
Steroidogenic Acute Regulatory

Abstract The most severe form of congenital adrenal hyperplasia (CAH) is lipoid CAH. It was once thought that this disease was due to mutations in the cholesterol side-chain cleavage enzyme system, thus eliminating the ability to convert cholesterol to pregnenolone, causing a complete absence of steroid hormone production. We recently showed that lipoid CAH is due to mutations in the steroidogenic acute regulatory (StAR) protein, thus preventing acutely stimulated adrenal and gonadal responses to tropic stimulation. However, this lesion may permit low levels of StAR-independent steroidogenesis to persist until the accumulation of intracellular lipid deposits destroys steroidogenic capacity. This model would predict that the steroidogenic cells of the ovaries of affected 46,XX females should remain undamaged until puberty, at which time low levels of StAR-independent estrogen biosynthesis should be detectable. We describe a 15.5-yr-old 46,XX female with a classic history of lipoid CAH who underwent spontaneous feminization and cyclical vaginal bleeding beginning at age 13. Genetic analysis of the patient and her parents showed that she was homozygous for the novel StAR frameshift mutation 261delT. This is the first adolescent female with lipoid CAH who has undergone spontaneous feminization and who has been analyzed genetically. Finding an inactive StAR gene in this patient confirms our two-hit model of the pathogenesis of lipoid CAH, in which loss of StAR activity initially preserves StAR-independent steroidogenesis, which is lost only after cells undergo chronic tropic stimulation and subsequent damage from accumulation of cholesterol esters.

scholarly journals Short term regulation of aldosterone secretion after stimulation and suppression experiments in mice

2009 ◽  
Vol 42 (5) ◽  
pp. 407-413 ◽  
Author(s):  
Ariadni Spyroglou ◽  
Jenny Manolopoulou ◽  
Sibylle Wagner ◽  
Martin Bidlingmaier ◽  
Martin Reincke ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Regulatory Protein ◽  
Zona Glomerulosa ◽  
Mrna Levels ◽  
Aldosterone Secretion ◽  
Sham Injection ◽  
Chain Cleavage ◽  
Sustained Reduction ◽  
Cleavage Enzyme ◽  
Steroidogenic Acute Regulatory

Aldosterone is synthesized acutely from the zona glomerulosa cells upon stimulation by the renin–angiotensin–aldosterone system. Several enzymes are involved in this steroidogenic process including the steroidogenic acute regulatory protein (StAR), P450 side chain cleavage enzyme (Cyp11a1), and aldosterone synthase (Cyp11b2) which has been demonstrated to be transcriptionally regulated by the nuclear transcription factors NGF1-B and Nurr1. We investigated the short time transcriptional regulation of these genes in wild-type mice at 10 min intervals for 1 h following application of 0.2 nmol angiotensin II (ANGII) or sodium chloride in comparison sham injections. Using real-time PCR a fast upregulation of adrenal Cyp11b2 expression (53±5% increase over baseline) could be observed 10 min after sham injection which was accompanied by a transient increase in aldosterone secretion while StAR and Cyp11a1 upregulation was delayed and more sustained. ANGII caused an increase of StAR and Cyp11a1 expression similar to that observed after sham injection while Cyp11b2 upregulation was more pronounced (10 min, 236±39%) and reflected ANGII induced stimulation of aldosterone output. Sodium challenge was followed by a sustained reduction of all three genes examined (Cyp11b2, 20 min, −63±6%) which was accompanied by a significant suppression of aldosterone secretion detectable after 60 min. While increases in NGF1-B mRNA levels were similar between the treatment groups, Nurr1 expression levels were induced only upon ANGII administration. These data suggest that acute regulation of aldosterone synthesis is accompanied by fast transcriptional modulation of steroidogenic enzymes and transcription factors that are likely to be involved in aldosterone secretion.

Transcriptional Regulation of Steroidogenic Genes: STARD1, CYP11A1 and HSD3B

2009 ◽  
Vol 234 (8) ◽  
pp. 880-907 ◽  
Author(s):  
Holly A. LaVoie ◽  
Steven R. King
Keyword(s):  
Transcriptional Regulation ◽  
Current Knowledge ◽  
Regulatory Protein ◽  
Side Chain ◽  
Combinatorial Regulation ◽  
Cytochrome P450scc ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Steroidogenic Acute Regulatory ◽  
Species Specific

Expression of the genes that mediate the first steps in steroidogenesis, the steroidogenic acute regulatory protein (STARD1), the cholesterol side-chain cleavage enzyme, cytochrome P450scc (CYP11A1) and 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (HSD3B), is tightly controlled by a battery of transcription factors in the adrenal cortex, the gonads and the placenta. These genes generally respond to the same hormones that stimulate steroid production through common pathways such as cAMP signaling and common actions on their promoters by proteins such as NR5A and GATA family members. However, there are distinct temporal, tissue and species-specific differences in expression between the genes that are defined by combinatorial regulation and unique promoter elements. This review will provide an overview of the hormonal and transcriptional regulation of the STARD1, CYP11A1 and specific steroidogenic HSD3B genes in the adrenal, testis, ovary and placenta and discuss the current knowledge regarding the key transcriptional factors involved.

Congenital adrenal hyperplasia

2011 ◽  
pp. 865-878
Author(s):  
Nils Krone
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Regulatory Protein ◽  
Signs And Symptoms ◽  
Adrenal Hyperplasia ◽  
Steroidogenic Enzymes ◽  
Autosomal Recessive Disorders ◽  
Chain Cleavage ◽  
Adrenal Steroidogenesis ◽  
Steroidogenic Acute Regulatory ◽  
Recessive Disorders

Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive disorders of steroidogenesis caused by defects in steroidogenic enzymes involved in glucocorticoid synthesis or in enzymes providing cofactors to steroidogenic enzymes (1, 2). Congenital lipoid adrenal hyperplasia (CLAH) caused by steroidogenic acute regulatory protein (StAR) deficiency is distinct in origin and presentation from the conventional variants of CAH, with the unique feature of lipid accumulation subsequently leading to destruction of adrenal function. This chapter will also mention aldosterone synthase deficiency, which is the only defect in adrenal steroidogenesis causing deficient mineralocorticoid biosynthesis without affecting glucocorticoid biosynthesis. The disorder cannot strictly be considered a CAH variant as it does not result in increased ACTH drive and thus not in adrenal hyperplasia. Novel forms of CAH have emerged during recent years. These include P450 oxidoreductase deficiency (ORD), P450 side-chain cleavage (CYP11A1) deficiency, the nonclassic form of CLAH (StAR deficiency), and apparent cortisone reductase deficiency. All forms of congenital adrenal hyperplasia resemble a disease continuum spanning from mild nonclassic presentations to classic onset with severe signs and symptoms.

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