ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Adrenal steroid biosynthesis

Adrenal steroid biosynthesis
Author:
Hershel Raff, PhD
Section Editor:
Lynnette K Nieman, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Jan 2024.
This topic last updated: May 05, 2022.

INTRODUCTION — The primary action of corticotropin (adrenocorticotropin; ACTH) on the adrenal cortex is to increase cortisol secretion by increasing its synthesis; intra-adrenal cortisol storage is minimal [1]. The major adrenal steroid hormones are synthesized in different areas of the adrenal cortex: glucocorticoids (particularly cortisol) in the zona fasciculata (ZF); androgens and estrogens in the zona reticularis (ZR); and aldosterone in the zona glomerulosa (ZG) (figure 1). The steps involved in the production of adrenal steroids will be reviewed here.

An appreciation of these pathways serves as the basis for understanding the different forms of congenital adrenal hyperplasia (CAH) and isolated hypoaldosteronism in which there are defects in the function of the enzymes involved in adrenal steroid hormone synthesis. It is also critical for understanding the mechanisms of action of drugs directed at reducing cortisol synthesis in patients with Cushing syndrome [2]. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)

MECHANISM OF ACTH ACTION — Corticotropin (ACTH) acts by binding to a specific cell-surface receptor, the melanocortin 2 receptor (MC2R) [3]. ACTH upregulates expression of these receptors, thereby increasing the steroidogenic response to further ACTH stimulation [4].

Failure of MC2R to activate in response to ACTH causes familial glucocorticoid deficiency (FGD), a rare autosomal recessive disorder characterized by severe cortisol deficiency with high plasma ACTH concentrations and normal mineralocorticoid levels. MC2R mutations resulting in effective loss of the receptor function are responsible for FGD type 1, which accounts for up to 25 percent of all FGD cases [5]. (See "Causes of primary adrenal insufficiency in children", section on 'Familial glucocorticoid deficiency'.)

The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small, single-pass transmembrane proteins; MRAP is a key accessory factor for the functional expression of the MC2R/ACTH receptor. The clinical observation that 20 percent of FGD cases are due to inactivating MRAP mutations highlights the importance of MRAP in adrenal gland physiology [6].

ACTH binding to its receptors activates adenylyl cyclase, increasing cyclic AMP (cAMP) production, which in turn stimulates cAMP-dependent protein kinase (protein kinase A) and phosphorylation of a number of proteins.

CHOLESTEROL SUBSTRATE — Cholesterol is the substrate for the synthesis of all steroid hormones. Steroidogenesis requires coordinated regulation of the cellular uptake, transport, and utilization of cholesterol followed by a series of unique biosynthetic steps. These processes are coordinated by the sterol regulatory element binding proteins (SREBPs), a family of basic helix-loop-helix transcriptional regulators that are also involved in lipid metabolism and adipocyte differentiation [7]. The cells of the adrenal cortex can either take up cholesterol from the circulation or synthesize cholesterol de novo from acetate. In humans, cholesterol for adrenal steroidogenesis is taken up from the bloodstream as:

Serum low-density lipoproteins (LDL) [8-10], which are delivered to the interior of adrenocortical cells via specific cell-surface receptors for LDL [11,12].

High-density lipoprotein (HDL) cholesterol can be a source of substrate for human adrenal steroidogenesis. In patients in whom delivery of LDL cholesterol to the adrenal is impaired, basal adrenal steroidogenesis is normal. Patients with abetalipoproteinemia, a heritable deficiency of apolipoprotein B production and no LDL in serum, and patients with familial hypercholesterolemia caused by defects in the LDL receptor system have normal basal cortisol production [13,14]. Under normal physiologic conditions, LDL is the primary source of cholesterol for steroid biosynthesis [10,15].

A receptor system for HDL, SR-B1 (scavenger receptor, class B, type 1), transfers HDL cholesterol into cells without endocytosis of the entire lipoprotein particle, as occurs with LDL [16]. SR-B1-knockout mice have lipid-depleted adrenocortical cells and high serum HDL cholesterol concentrations [17]. The human homolog of SR-B1, called CLA-1, is expressed in liver and steroidogenic cells and transfers HDL cholesterol into cultured adrenal cells [18,19]. Within a large kindred, individuals with a heterozygous missense mutation in SR-B1 were found to have increased HDL levels, decreased urinary excretion of cortisol metabolites, decreased cortisol response to cosyntropin, and symptoms consistent with adrenal insufficiency when compared with individuals without the mutation [20].

Expression of SR-B1 is regulated as follows:

It is stimulated or positively regulated by activation of adenylyl cyclase, the transcription factor steroidogenic factor 1 (SF-1), SREBP-1a, and cofactors such as promoter-specific transcription factor (Sp1). Patients heterozygous for inactivating SF-1 mutations have adrenal insufficiency [21].

It is suppressed by the intracellular level of cholesterol and negatively regulated by the dose-sensitive sex reversal adrenal hypoplasia gene on the X chromosome, gene 1 (DAX-1) transcription factor [22,23]. Dax-1(-/Y) mice have normal basal serum corticosterone levels and have greater corticosterone responses to corticotropin (ACTH) than wild-type mice [24].

Free cholesterol is generated from LDL sources of cholesteryl esters by lysosomal acid lipase (LAL). Mutations in LAL (encoded by the LIPA gene) cause LAL deficiency (Wolman disease/cholesteryl ester storage disease). (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

CORTISOL BIOSYNTHESIS IN THE ZONA FASCICULATA (ZF) — Four distinct cytochrome P450 enzymes are involved in adrenal corticosteroid biosynthesis, as shown in the middle panel of the figure (figure 1). They are members of a large family of cytochrome P450 oxidative enzymes, so named because they have a characteristic 450 nm absorbance maximum when reduced with carbon monoxide. These enzymes serve a variety of biologic functions [25]. They transfer electrons from NADPH, provided by an electron-transport protein intermediary, to molecular oxygen with concomitant oxygenation of a number of substrates. The nomenclature of these enzymes has been changed as a result of insights gained from molecular cloning. Terminology based on the name of the gene, previous designation based on the P450 structure and function, and common functional names are shown in the table (table 1).

The substrates for the steroidogenic P450 enzymes are carbon atoms of the four-ring structures of cholesterol [25].

Each enzymatic step in cortisol biosynthesis is compartmentalized within the cell by virtue of the subcellular localization of the enzyme involved.

Pregnenolone synthesis by CYP11A1 — The rate-limiting process in steroidogenesis is the transport of free cholesterol through the cytosol to the inner mitochondrial membrane, the site of the cholesterol side-chain cleavage enzyme (CYP11A1) that catalyzes the first step in steroidogenesis (figure 1).

Cholesterol transport into mitochondria is mediated by a protein designated StAR (steroidogenic acute regulatory protein) [26-28]; in the absence of this protein, steroidogenesis is severely impaired [26].

Basal and cyclic AMP (cAMP)-stimulated StAR activities are increased by steroidogenic factor 1 (SF-1) acting in concert with promoter-specific transcription factor (Sp1) [29].

Another multimeric protein complex, the translocator protein (TSPO, 18-kDa) formerly known as the peripheral benzodiazepine receptor (PBR), may also be involved in the transfer of cholesterol into the mitochondrion [30,31]. Therefore, TSPO may be necessary for corticotropin (ACTH)-mediated steroidogenesis [32].

Within mitochondria, pregnenolone is derived from cholesterol by removal of the side-chain at C20 catalyzed by a single enzyme derived from the CYP11A1 gene [33].

The electrons transferred by CYP11A1 during the side-chain cleavage reaction are provided through an electron transport system comprised of adrenodoxin, which exists in a soluble form in mitochondria, and adrenodoxin reductase, a mitochondrial membrane-bound flavoprotein. Adrenodoxin reductase accepts electrons from an NADPH-dependent cytochrome P450 reductase and transfers them to adrenodoxin, which serves as a shuttle to deliver reducing equivalents to various P450 enzymes [34,35].

Conversion of pregnenolone to progesterone — Newly synthesized pregnenolone is converted to progesterone by dehydrogenation of the 3-hydroxyl group of pregnenolone and isomerization of the double bond at C5 (figure 1). These reactions are catalyzed by 3-beta-hydroxysteroid dehydrogenase 2 (HSD3B2), a microsomal (endoplasmic reticulum) membrane-associated enzyme that is expressed only in the adrenals and gonads (figure 1) [36].

Progesterone to 17-alpha-hydroxyprogesterone — CYP17 is a microsomal enzyme that catalyzes both hydroxylation at C17 of progesterone or pregnenolone (17-alpha-hydroxylase activity) and cleavage of the residual two-carbon side-chain at C17 (17,20-lyase activity) [37]. However, in the cortisol pathway, 17,20-lyase activity is minimal and the ZF is not a major source of androgens [15].

The dual function of CYP17 allows steroidogenesis to be directed to several different pathways:

17-alpha-hydroxylated substrates with the side-chain intact are glucocorticoid precursors (figure 1). The absence of cytochrome b5 in the ZF limits 17,20-lyase activity.

Generation of C19 steroids by both 17-alpha-hydroxylase and 17,20-lyase activities (the latter activity due to the presence of cytochrome b5) directs substrate towards androgen synthesis in the zona reticularis (ZR), which is shown in the lower panel of the figure (figure 1). Not shown is that the ZR does express a small amount of aromatase activity and can produce estrogens, although most circulating estrogen in healthy males is from peripheral conversion of androgens and, in reproductive age females, from the ovaries.

In the zona glomerulosa (ZG), which lacks either form of CYP17 activity, pregnenolone is converted into aldosterone; this is shown in the upper panel of the figure (figure 1).

17-alpha-hydroxyprogesterone to 11-deoxycortisol — Both progesterone and 17-alpha-hydroxyprogesterone are 21-hydroxylated by a single CYP21A2 enzyme (21-hydroxylase) located in the smooth endoplasmic reticulum [38]. There are two related CYP21 genes on chromosome 6p21.3 [39], but only one is active [40]. The inactive form is a pseudogene (CYP21A1P), which is transcribed into an mRNA that does not code for a functional protein [41-43].

Conversion of 11-deoxycortisol to cortisol — The last step in cortisol biosynthesis is the 11-beta-hydroxylation of 11-deoxycortisol, a reaction catalyzed by the mitochondrial enzyme CYP11B1. Like CYP11A1, the other P450 enzyme of the inner mitochondrial membrane, CYP11B1 receives electrons from NADPH via adrenodoxin reductase and adrenodoxin [44].

CYP11B1 is nearly identical to the CYP11B2 enzyme responsible for the terminal steps of aldosterone synthesis, except that it lacks the ability to convert corticosterone to aldosterone. CYP11B1 is more closely related to CYP11A1 than to the microsomal P450 enzymes [45,46]. CYP11B1 expression is increased by cAMP and SF-1 [47].

ALDOSTERONE BIOSYNTHESIS IN THE ZONA GLOMERULOSA (ZG) — Progesterone is also the substrate for mineralocorticoid synthesis, as shown in the upper panel of the figure (figure 1). In the ZG, progesterone is hydroxylated at C21 by CYP21A2 to yield deoxycorticosterone. All three terminal steps in the conversion of this intermediate to aldosterone (11-beta-hydroxylation, 18-hydroxylation, and 18-methyl oxidation) are catalyzed by a single mitochondrial P450 enzyme, CYP11B2 (aldosterone synthase, P450c11as) [48,49]. The human CYP11B2 is encoded by a gene closely related to CYP11B1 (11-beta-hydroxylase), with over 90 percent homology at the protein level. The CYP11B2 gene is also located on chromosome 8q24.3, near the CYP11B1 gene [50]. (See "Familial hyperaldosteronism".)

The ZG is well adapted for the production of aldosterone:

It has a low concentration of CYP17A1 (17-hydroxylase), the enzyme that directs substrate along the pathways to cortisol and androgen synthesis.

It is the only adrenocortical zone that has the enzyme required for the sequential conversion of deoxycorticosterone to aldosterone [49].

The restriction of CYP11B2 (aldosterone synthase) expression to the ZG is very important physiologically. Expression of the gene in the zona fasciculata (ZF) would render aldosterone production subject to regulation by corticotropin (ACTH). An analogous situation occurs in glucocorticoid-remediable aldosteronism in which the ACTH-regulated promoter of CYP11B1 is fused into the enzyme-coding exons of CYP11B2 resulting in a chimeric protein expressed in the zona fasciculata with ACTH-driven aldosterone synthase activity [51,52]. (See "Familial hyperaldosteronism".)

In healthy subjects, angiotensin II and a small increase in the serum potassium concentration are the primary stimuli to aldosterone release. Steroidogenic factor 1 (SF-1), which stimulates CYP11B1 gene expression, does not alter the expression of the CYP11B2 gene [47]. Activity of steroidogenic acute regulatory protein (StAR), which increases aldosterone synthesis by mediating cholesterol transport into the mitochondria, is stimulated by increased intracellular calcium concentration [30]. Aldosterone release is also stimulated acutely by ACTH, which is the basis of evaluating ZG function with the cosyntropin stimulation test. (See "Diagnosis of adrenal insufficiency in adults".)

ADRENAL ANDROGEN BIOSYNTHESIS IN THE ZONA RETICULARIS (ZR) — Steroids with 19 carbon atoms and androgenic activity are synthesized by the adrenals. In fact, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the most abundant products of the adrenal glands. They are formed in the ZR, which has no 3-beta-hydroxysteroid dehydrogenase 2 (HSD3B2) [53], from 17-alpha-hydroxypregnenolone by the 17,20-lyase activity of CYP17A1.

Androstenedione, another weak androgen, is produced mainly in peripheral tissues; this process is shown in the lower panel of the figure (figure 1). There is minimal synthesis of testosterone in the normal adrenal gland. (See "Adrenal hyperandrogenism".)

ACUTE AND CHRONIC ACTIONS OF ACTH — The effects of corticotropin (ACTH) on steroidogenesis can be divided into acute effects, which occur within minutes, and chronic effects, which occur in hours or days [54].

The acute effect of ACTH is to increase cholesterol transfer from the cytoplasm to the inner mitochondrial membrane so that it can be converted to delta-5-pregnenolone by CYP11A1. This is the initial and rate-limiting step in adrenal steroid biosynthesis (figure 1) [54]. Increases in cholesterol transport depend on the ACTH-stimulated increase in cyclic AMP (cAMP) generation and phosphorylation of steroidogenic acute regulatory protein (StAR) [28,55-57]. The chronic effects of ACTH involve increased synthesis of most of the enzymes of the steroidogenic pathway and more general actions on adrenocortical cell protein, RNA and DNA synthesis, and cell growth [25]. In bovine adrenocortical cells, ACTH increases the rate of synthesis of all steroidogenic CYP enzymes, including CYP11A1, CYP17, CYP21A2, and CYP11B1 [58], plus the electron-transport protein adrenodoxin [59] and adrenodoxin reductase [54].

ACTH also increases the synthesis of StAR as well as other proteins required for steroidogenesis. These include the low-density lipoprotein (LDL) and high-density lipoprotein (HDL) receptors [60], adrenodoxin [60], and sterol-carrier protein (SCP2) [61].

ACTH action on glomerulosa cells is complex. It initially stimulates and later suppresses aldosterone synthase gene expression. For this reason, exogenous ACTH stimulation can be used to assess zona glomerulosa (ZG) function [62,63]. (See "Diagnosis of adrenal insufficiency in adults".)

OVERVIEW OF CONGENITAL ADRENAL HYPERPLASIA — Defects in cortisol biosynthesis result in a group of syndromes termed congenital adrenal hyperplasia (figure 1). These disorders are all inherited as autosomal recessive traits and are reviewed in detail separately [30]. (See "Clinical manifestations and diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children" and "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias".)

The resulting decrease in cortisol production causes an increase in the secretion of corticotropin (ACTH), thereby stimulating the production of adrenal steroids up to and including the substrate for the defective enzyme. The clinical manifestations reflect one or more of the following:

Impaired synthesis of cortisol

Impaired synthesis of aldosterone

Increases in adrenal androgenic hormones (which can cause virilization) and in deoxycorticosterone (which has mineralocorticoid activity and can cause hypertension)

What follows is a brief review of the consequences of the different enzymatic defects, each of which is discussed in detail elsewhere (table 2).

Salt wasting and hyperkalemia, resulting from mineralocorticoid deficiency, occur in CYP21A2 deficiency, HSD3B2 deficiency, and congenital lipoid adrenal hyperplasia. Clinical cortisol deficiency is also present in infancy, but cortisol production may be sufficient in older children or adults. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)

Similar abnormalities occur as the sole finding with defects in aldosterone synthase; cortisol synthesis is intact in these disorders, which are not considered a form of congenital adrenal insufficiency. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)".)

Hypertension and frequently hypokalemia due to excess deoxycorticosterone is the major abnormality in CYP17 (17-alpha-hydroxylase) and CYP11B1 deficiencies. As a result of increased ACTH stimulation, cortisol production may be sufficient to prevent development of adrenal insufficiency. (See "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency' and "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)

In addition to the abnormalities described above, virilization of female fetuses or hirsutism and virilization of females later in life occurs in CYP21A2 (21-hydroxylase) deficiency and in CYP11B1 (11-beta-hydroxylase) deficiency because of increased androgen synthesis. (See "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Uncommon congenital adrenal hyperplasias", section on '11-beta-hydroxylase deficiency'.)

In addition to the abnormalities described above, hypogonadism and disorders of sex development can be a consequence of CYP17 deficiency, HSD3B2 deficiency, or congenital lipoid adrenal hyperplasia. (See "Uncommon congenital adrenal hyperplasias", section on 'Lipoid congenital adrenal hyperplasia'.)

SUMMARY

The primary action of steroidogenic stimuli (eg, corticotropin [ACTH] and angiotensin II) is to increase end-product release into the blood stream by increasing steroid synthesis; intra-adrenal steroid storage is minimal.

The major adrenal steroid hormones are synthesized in different anatomic zones of the adrenal cortex (figure 1):

Glucocorticoids (particularly cortisol) in the zona fasciculata (ZF)

Androgens in the zona reticularis (ZR)

Aldosterone in the zona glomerulosa (ZG)

Cholesterol is the substrate for the synthesis of all steroid hormones. The cells of the adrenal cortex can either take up cholesterol from the circulation or synthesize cholesterol de novo from acetate. (See 'Cholesterol substrate' above.)

Four distinct cytochrome P450 enzymes are involved in adrenal corticosteroid biosynthesis (table 1).

The steps of cortisol biosynthesis are shown in the figure (figure 1). (See 'Cortisol biosynthesis in the zona fasciculata (ZF)' above.)

The steps of adrenal androgen and aldosterone biosynthesis are reviewed above (figure 1). (See 'Aldosterone biosynthesis in the zona glomerulosa (ZG)' above and 'Adrenal androgen biosynthesis in the zona reticularis (ZR)' above.)

Inherited defects in the enzymatic steps of cortisol biosynthesis result in a group of syndromes termed congenital adrenal hyperplasia (figure 1). These disorders are inherited as autosomal recessive traits. An overview of the different forms of congenital adrenal hyperplasia is found above. (See 'Overview of congenital adrenal hyperplasia' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

  1. Dickerman Z, Grant DR, Faiman C, Winter JS. Intraadrenal steroid concentrations in man: zonal differences and developmental changes. J Clin Endocrinol Metab 1984; 59:1031.
  2. Fleseriu M. Medical treatment of Cushing disease: new targets, new hope. Endocrinol Metab Clin North Am 2015; 44:51.
  3. Cone RD, Mountjoy KG. Molecular genetics of the ACTH and melanocyte-stimulating hormone receptors. Trends Endocrinol Metab 1993; 4:242.
  4. Penhoat A, Lebrethon MC, Bégeot M, Saez JM. Regulation of ACTH receptor mRNA and binding sites by ACTH and angiotensin II in cultured human and bovine adrenal fasciculata cells. Endocr Res 1995; 21:157.
  5. Clark AJ, Metherell LA, Cheetham ME, Huebner A. Inherited ACTH insensitivity illuminates the mechanisms of ACTH action. Trends Endocrinol Metab 2005; 16:451.
  6. Novoselova TV, Jackson D, Campbell DC, et al. Melanocortin receptor accessory proteins in adrenal gland physiology and beyond. J Endocrinol 2013; 217:R1.
  7. Jeon TI, Osborne TF. SREBPs: metabolic integrators in physiology and metabolism. Trends Endocrinol Metab 2012; 23:65.
  8. Borkowski AJ, Levin S, Delcroix C, et al. Blood cholesterol and hydrocortisone production in man: quantitative aspects of the utilization of circulating cholesterol by the adrenals at rest and under adrenocorticotropin stimulation. J Clin Invest 1967; 46:797.
  9. Bolté E, Coudert S, Lefebvre Y. Steroid production from plasma cholesterol. II. In vivo conversion of plasma cholesterol to ovarian progesterone and adrenal C19 and C21 steroids in humans. J Clin Endocrinol Metab 1974; 38:394.
  10. Gwynne JT, Strauss JF 3rd. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endocr Rev 1982; 3:299.
  11. Faust JR, Goldstein JL, Brown MS. Receptor-mediated uptake of low density lipoprotein and utilization of its cholesterol for steroid synthesis in cultured mouse adrenal cells. J Biol Chem 1977; 252:4861.
  12. Goldstein JL, Anderson RG, Brown MS. Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature 1979; 279:679.
  13. Illingworth DR, Kenny TA, Orwoll ES. Adrenal function in heterozygous and homozygous hypobetalipoproteinemia. J Clin Endocrinol Metab 1982; 54:27.
  14. Illingworth DR, Lees AM, Lees RS. Adrenal cortical function in homozygous familial hypercholesterolemia. Metabolism 1983; 32:1045.
  15. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 2011; 32:81.
  16. Acton S, Rigotti A, Landschulz KT, et al. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996; 271:518.
  17. Rigotti A, Trigatti BL, Penman M, et al. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci U S A 1997; 94:12610.
  18. Imachi H, Murao K, Sato M, et al. CD36 LIMPII analogous-1, a human homolog of the rodent scavenger receptor B1, provides the cholesterol ester for steroidogenesis in adrenocortical cells. Metabolism 1999; 48:627.
  19. Murao K, Terpstra V, Green SR, et al. Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes. J Biol Chem 1997; 272:17551.
  20. Vergeer M, Korporaal SJ, Franssen R, et al. Genetic variant of the scavenger receptor BI in humans. N Engl J Med 2011; 364:136.
  21. Biason-Lauber A, Schoenle EJ. Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency. Am J Hum Genet 2000; 67:1563.
  22. Cao G, Zhao L, Stangl H, et al. Developmental and hormonal regulation of murine scavenger receptor, class B, type 1. Mol Endocrinol 1999; 13:1460.
  23. Lopez D, Shea-Eaton W, Sanchez MD, McLean MP. DAX-1 represses the high-density lipoprotein receptor through interaction with positive regulators sterol regulatory element-binding protein-1a and steroidogenic factor-1. Endocrinology 2001; 142:5097.
  24. Babu PS, Bavers DL, Beuschlein F, et al. Interaction between Dax-1 and steroidogenic factor-1 in vivo: increased adrenal responsiveness to ACTH in the absence of Dax-1. Endocrinology 2002; 143:665.
  25. Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev 1988; 9:295.
  26. Lin D, Sugawara T, Strauss JF 3rd, et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 1995; 267:1828.
  27. Waterman MR. A rising StAR: an essential role in cholesterol transport. Science 1995; 267:1780.
  28. Stocco DM, Clark BJ. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev 1996; 17:221.
  29. Sugawara T, Saito M, Fujimoto S. Sp1 and SF-1 interact and cooperate in the regulation of human steroidogenic acute regulatory protein gene expression. Endocrinology 2000; 141:2895.
  30. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000; 21:245.
  31. Papadopoulos V, Baraldi M, Guilarte TR, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 2006; 27:402.
  32. Fan J, Campioli E, Midzak A, et al. Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation. Proc Natl Acad Sci U S A 2015; 112:7261.
  33. Chung BC, Matteson KJ, Voutilainen R, et al. Human cholesterol side-chain cleavage enzyme, P450scc: cDNA cloning, assignment of the gene to chromosome 15, and expression in the placenta. Proc Natl Acad Sci U S A 1986; 83:8962.
  34. Kimura T, Suzuki K. Components of the electron transport system in adrenal steroid hydroxylase. Isolation and properties of non-heme iron protein (adrenodoxin). J Biol Chem 1967; 242:485.
  35. Kominami S, Hara H, Ogishima T, Takemori S. Interaction between cytochrome P-450 (P-450C21) and NADPH-cytochrome P-450 reductase from adrenocortical microsomes in a reconstituted system. J Biol Chem 1984; 259:2991.
  36. Penning TM. Molecular endocrinology of hydroxysteroid dehydrogenases. Endocr Rev 1997; 18:281.
  37. Yanase T, Simpson ER, Waterman MR. 17 alpha-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition. Endocr Rev 1991; 12:91.
  38. Kominami S, Ochi H, Kobayashi Y, Takemori S. Studies on the steroid hydroxylation system in adrenal cortex microsomes. Purification and characterization of cytochrome P-450 specific for steroid C-21 hydroxylation. J Biol Chem 1980; 255:3386.
  39. White PC, Chaplin DD, Weis JH, et al. Two steroid 21-hydroxylase genes are located in the murine S region. Nature 1984; 312:465.
  40. White PC, New MI, Dupont B. HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation. Proc Natl Acad Sci U S A 1984; 81:7505.
  41. White PC, Grossberger D, Onufer BJ, et al. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A 1985; 82:1089.
  42. Bristow J, Gitelman SE, Tee MK, et al. Abundant adrenal-specific transcription of the human P450c21A "pseudogene". J Biol Chem 1993; 268:12919.
  43. Chang SF, Chung BC. Difference in transcriptional activity of two homologous CYP21A genes. Mol Endocrinol 1995; 9:1330.
  44. Chu JW, Kimura T. Studies on adrenal steroid hydroxylases. Molecular and catalytic properties of adrenodoxin reductase (a flavoprotein). J Biol Chem 1973; 248:2089.
  45. Chua SC, Szabo P, Vitek A, et al. Cloning of cDNA encoding steroid 11 beta-hydroxylase (P450c11). Proc Natl Acad Sci U S A 1987; 84:7193.
  46. John ME, John MC, Simpson ER, Waterman MR. Regulation of cytochrome P-45011 beta gene expression by adrenocorticotropin. J Biol Chem 1985; 260:5760.
  47. Wang XL, Bassett M, Zhang Y, et al. Transcriptional regulation of human 11beta-hydroxylase (hCYP11B1). Endocrinology 2000; 141:3587.
  48. White PC, Curnow KM, Pascoe L. Disorders of steroid 11 beta-hydroxylase isozymes. Endocr Rev 1994; 15:421.
  49. White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med 1994; 331:250.
  50. Taymans SE, Pack S, Pak E, et al. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3. J Clin Endocrinol Metab 1998; 83:1033.
  51. Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355:262.
  52. Pascoe L, Curnow KM, Slutsker L, et al. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci U S A 1992; 89:8327.
  53. Endoh A, Kristiansen SB, Casson PR, et al. The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 1996; 81:3558.
  54. Simpson ER, Waterman MR. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu Rev Physiol 1988; 50:427.
  55. Clark BJ, Ranganathan V, Combs R. Steroidogenic acute regulatory protein expression is dependent upon post-translational effects of cAMP-dependent protein kinase A. Mol Cell Endocrinol 2001; 173:183.
  56. Manna PR, Stetson CL, Slominski AT, Pruitt K. Role of the steroidogenic acute regulatory protein in health and disease. Endocrine 2016; 51:7.
  57. Clark BJ. ACTH Action on StAR Biology. Front Neurosci 2016; 10:547.
  58. Kramer RE, Simpson ER, Waterman MR. Induction of 11 beta-hydroxylase by corticotropin in primary cultures of bovine adrenocortical cells. J Biol Chem 1983; 258:3000.
  59. Kramer RE, Anderson CM, Peterson JA, et al. Adrenodoxin biosynthesis by bovine adrenal cells in monolayer culture. Induction by adrenocorticotropin. J Biol Chem 1982; 257:14921.
  60. Plump AS, Erickson SK, Weng W, et al. Apolipoprotein A-I is required for cholesteryl ester accumulation in steroidogenic cells and for normal adrenal steroid production. J Clin Invest 1996; 97:2660.
  61. Trzeciak WH, Simpson ER, Scallen TJ, et al. Studies on the synthesis of sterol carrier protein-2 in rat adrenocortical cells in monolayer culture. Regulation by ACTH and dibutyryl cyclic 3',5'-AMP. J Biol Chem 1987; 262:3713.
  62. Umakoshi H, Xiaomei Y, Ichijo T, et al. Reassessment of the cosyntropin stimulation test in the confirmatory diagnosis and subtype classification of primary aldosteronism. Clin Endocrinol (Oxf) 2017; 86:170.
  63. Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing's syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr Physiol 2014; 4:739.
Topic 120 Version 25.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟