Regulation of Adrenal Steroidogenesis

  • Marjut Pihlajoki
  • Markku Heikinheimo
  • David B. Wilson
Part of the Contemporary Endocrinology book series (COE)


The human adrenal cortex is divided into concentric zones: the zona glomerulosa produces aldosterone, the zona fasciculata secretes cortisol, and the zona reticularis synthesizes 19-carbon (C19) androgen precursors. Angiotensin II (Ang II) and extracellular K+ are the principal stimuli of aldosterone secretion, whereas adrenocorticotropic hormone (ACTH) is the main stimulus of cortisol and C19 steroid production. Most of the cholesterol used for the biosynthesis of adrenal steroids is derived from receptor-mediated endocytosis of plasma low-density lipoproteins (LDL). In late endosomes, LDL-derived cholesteryl esters (CEs) are hydrolyzed by lysosomal acid lipase. The resultant-free cholesterol can be re-esterified by sterol O-acetyltransferase and stored in lipid droplets. Cholesterol can be liberated from stored CEs by hormone-sensitive lipase, an enzyme activated in response to Ang II or ACTH or stimulation. To initiate steroidogenesis, cholesterol undergoes facilitated transport from a replenishable pool in the outer mitochondrial membrane to the inner mitochondrial membrane, where CYP11A1 catalyzes the conversion of cholesterol to pregnenolone. The remaining steps of steroidogenesis take place in the endoplasmic reticulum and mitochondria. This chapter highlights the regulation of adrenal steroidogenesis. Key intracellular signaling molecules, including second messengers and downstream transcription factors, are reviewed. Pathological conditions associated with aberrant production of adrenal steroids are discussed.


Adrenal cortex Adrenal gland Adrenocorticotropic hormone Aldosterone Cortisol Dehydroepiandrosterone Zona glomerulosa Zona fasciculata Zona reticularis 



We thank Karin Sanders, Sara Galac, and Audrey Odom John for the assistance with figure preparation. We thank Rebecca Cochran and Paul Hruz for reviewing the manuscript. This work was supported by the Sigrid Jusélius Foundation, the Academy of Finland, Department of Defense grants PC141008 and OC150105, Prostate Cancer Foundation, and the Paulo Foundation.


  1. 1.
    Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32:81–151.PubMedCrossRefGoogle Scholar
  2. 2.
    Turcu AF, Auchus RJ. Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin N Am. 2015;44:275–96.CrossRefGoogle Scholar
  3. 3.
    Miller WL. StAR search--what we know about how the steroidogenic acute regulatory protein mediates mitochondrial cholesterol import. Mol Endocrinol. 2007b;21:589–601.PubMedCrossRefGoogle Scholar
  4. 4.
    Bornstein SR, Wilson DB. Anatomy of the adrenal cortex. In: Martini L, Huhtaniemi I, editors. Reference module in biomedical sciences. Oxford: Elsevier; 2015.Google Scholar
  5. 5.
    Vinson GP. Functional zonation of the adult mammalian adrenal cortex. Front Neurosci. 2016;10:238.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Monticone S, Auchus RJ, Rainey WE. Adrenal disorders in pregnancy. Nat Rev Endocrinol. 2012;8:668–78.PubMedCrossRefGoogle Scholar
  7. 7.
    Goto M, Piper HK, Marcos J, Wood PJ, Wright S, Postle AD, Cameron IT, Mason JI, Wilson DI, Hanley NA. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Invest. 2006;116:953–60.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev. 1997;18:378–403.PubMedGoogle Scholar
  9. 9.
    Quinn TA, Ratnayake U, Dickinson H, Castillo-Melendez M, Walker DW. The feto-placental unit, and potential roles of dehydroepiandrosterone (DHEA) in prenatal and postnatal brain development: a re-examination using the spiny mouse. J Steroid Biochem Mol Biol. 2016;160:204–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Peter M, Dorr HG, Sippell WG. Changes in the concentrations of dehydroepiandrosterone sulfate and estriol in maternal plasma during pregnancy: a longitudinal study in healthy women throughout gestation and at term. Horm Res. 1994;42:278–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Rainey WE, Rehman KS, Carr BR. The human fetal adrenal: making adrenal androgens for placental estrogens. Semin Reprod Med. 2004;22:327–36.PubMedCrossRefGoogle Scholar
  12. 12.
    Sirianni R, Mayhew BA, Carr BR, Parker CR Jr, Rainey WE. Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells. J Clin Endocrinol Metab. 2005;90:5393–400.PubMedCrossRefGoogle Scholar
  13. 13.
    Turcu A, Smith JM, Auchus R, Rainey WE. Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions. Compr Physiol. 2014;4:1369–81.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Xing Y, Lerario AM, Rainey W, Hammer GD. Development of adrenal cortex zonation. Endocrinol Metab Clin N Am. 2015;44:243–74.CrossRefGoogle Scholar
  15. 15.
    Ansurudeen I, Kopf PG, Gauthier KM, Bornstein SR, Cowley AW Jr, Campbell WB. Aldosterone secretagogues increase adrenal blood flow in male rats. Endocrinology. 2014;155:127–32.PubMedCrossRefGoogle Scholar
  16. 16.
    Bassett JR, West SH. Vascularization of the adrenal cortex: its possible involvement in the regulation of steroid hormone release. Microsc Res Tech. 1997;36:546–57.PubMedCrossRefGoogle Scholar
  17. 17.
    Bollag WB. Regulation of aldosterone synthesis and secretion. Compr Physiol. 2014;4:1017–55.PubMedCrossRefGoogle Scholar
  18. 18.
    Cole TJ, Terella L, Morgan J, Alexiadis M, Yao YZ, Enriori P, Young MJ, Fuller PJ. Aldosterone-mediated renal sodium transport requires intact mineralocorticoid receptor DNA-binding in the mouse. Endocrinology. 2015;156:2958–68.PubMedCrossRefGoogle Scholar
  19. 19.
    Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol. 2013;9:459–69.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Gomez-Sanchez CE. Non renal effects of aldosterone. Steroids. 2014a;91:1–2.PubMedCrossRefGoogle Scholar
  21. 21.
    Pacurari M, Kafoury R, Tchounwou PB, Ndebele K. The renin-angiotensin-aldosterone system in vascular inflammation and remodeling. Int J Inflam. 2014;2014:689360.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Brown NJ. This is not Dr. Conn's aldosterone anymore. Trans Am Clin Climatol Assoc. 2011;122:229–43.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Yates R, Katugampola H, Cavlan D, Cogger K, Meimaridou E, Hughes C, Metherell L, Guasti L, King P. Adrenocortical development, maintenance, and disease. Curr Top Dev Biol. 2013;106:239–312.PubMedCrossRefGoogle Scholar
  24. 24.
    Gallo-Payet N. 60 YEARS OF POMC: adrenal and extra-adrenal functions of ACTH. J Mol Endocrinol. 2016;56:T135–56.PubMedCrossRefGoogle Scholar
  25. 25.
    Arlt W, Stewart PM. Adrenal corticosteroid biosynthesis, metabolism, and action. Endocrinol Metab Clin N Am. 2005;34:293–313.CrossRefGoogle Scholar
  26. 26.
    Franchimont D. Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci. 2004;1024:124–37.PubMedCrossRefGoogle Scholar
  27. 27.
    Adams JB. Control of secretion and the function of C19-delta 5-steroids of the human adrenal gland. Mol Cell Endocrinol. 1985;41:1–17.PubMedCrossRefGoogle Scholar
  28. 28.
    Davison SL, Bell R. Androgen physiology. Semin Reprod Med. 2006;24:71–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Rainey WE, Nakamura Y. Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol. 2007;108(3–5):281–6.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Beuschlein F, Galac S, Wilson DB. Animal models of adrenocortical tumorigenesis. Mol Cell Endocrinol. 2012;351:78–86.PubMedCrossRefGoogle Scholar
  31. 31.
    Morohashi K, Zubair M. The fetal and adult adrenal cortex. Mol Cell Endocrinol. 2011;336:193–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Hershkovitz L, Beuschlein F, Klammer S, Krup M, Weinstein Y. Adrenal 20alpha-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology. 2007;148:976–88.PubMedCrossRefGoogle Scholar
  33. 33.
    Guasti L, Cavlan D, Cogger K, Banu Z, Shakur A, Latif S, King PJ. Dlk1 up-regulates Gli1 expression in male rat adrenal capsule cells through the activation of beta1 integrin and ERK1/2. Endocrinology. 2013b;154:4675–84.PubMedCrossRefGoogle Scholar
  34. 34.
    Galac S, Wilson DB. Animal models of adrenocortical tumorigenesis. Endocrinol Metab Clin N Am. 2015;44:297–310.CrossRefGoogle Scholar
  35. 35.
    Quinn TA, Ratnayake U, Dickinson H, Nguyen TH, McIntosh M, Castillo-Melendez M, Conley AJ, Walker DW. Ontogeny of the adrenal gland in the spiny mouse, with particular reference to production of the steroids cortisol and dehydroepiandrosterone. Endocrinology. 2013;154:1190–201.PubMedCrossRefGoogle Scholar
  36. 36.
    Pignatti E, Leng S, Carlone DL, Breault DT. Regulation of zonation and homeostasis in the adrenal cortex. Mol Cell Endocrinol. 2016;441:146–55.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Pihlajoki M, Dorner J, Cochran RS, Heikinheimo M, Wilson DB. Adrenocortical zonation, renewal, and remodeling. Front Endocrinol (Lausanne). 2015;6:27.Google Scholar
  38. 38.
    Walczak EM, Hammer GD. Regulation of the adrenocortical stem cell niche: implications for disease. Nat Rev Endocrinol. 2015;11:14–28.PubMedCrossRefGoogle Scholar
  39. 39.
    Gallo-Payet N, Guillon G. Regulation of adrenocortical function by vasopressin. Horm Metab Res. 1998;30:360–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Pattison JC, Abbott DH, Saltzman W, Conley AJ, Bird IM. Plasticity of the zona reticularis in the adult marmoset adrenal cortex: voyages of discovery in the new world. J Endocrinol. 2009;203:313–26.PubMedCrossRefGoogle Scholar
  41. 41.
    Topor LS, Asai M, Dunn J, Majzoub JA. Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2. J Clin Endocrinol Metab. 2011;96:E31–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Thomas JL, Rajapaksha M, Mack VL, DeMars GA, Majzoub JA, Bose HS. Regulation of human 3beta-hydroxysteroid dehydrogenase type 2 by adrenal corticosteroids and product-feedback by androstenedione in human adrenarche. J Pharmacol Exp Ther. 2015;352:67–76.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Bernichtein S, Alevizaki M, Huhtaniemi I. Is the adrenal cortex a target for gonadotropins? Trends Endocrinol Metab. 2008;19:231–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Teo AE, Garg S, Shaikh LH, Zhou J, Karet Frankl FE, Gurnell M, Happerfield L, Marker A, Bienz M, Azizan EA, Brown MJ. Pregnancy, primary Aldosteronism, and adrenal CTNNB1 mutations. N Engl J Med. 2015;373:1429–36.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Beuschlein F, Looyenga BD, Bleasdale SE, Mutch C, Bavers DL, Parlow AF, Nilson JH, Hammer GD. Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin-deficient mice. Mol Cell Biol. 2003;23:3951–64.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Vanttinen T, Liu J, Kuulasmaa T, Kivinen P, Voutilainen R. Expression of activin/inhibin signaling components in the human adrenal gland and the effects of activins and inhibins on adrenocortical steroidogenesis and apoptosis. J Endocrinol. 2003;178:479–89.PubMedCrossRefGoogle Scholar
  47. 47.
    Drelon C, Berthon A, Val P. Adrenocortical cancer and IGF2: is the game over or our experimental models limited? J Clin Endocrinol Metab. 2013;98:505–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Fottner C, Hoeflich A, Wolf E, Weber MM. Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis. Horm Metab Res. 2004;36:397–405.PubMedCrossRefGoogle Scholar
  49. 49.
    Crickard K, Ill CR, Jaffe RB. Control of proliferation of human fetal adrenal cells in vitro. J Clin Endocrinol Metab. 1981;53:790–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Guasti L, Candy Sze WC, McKay T, Grose R, King PJ. FGF signalling through Fgfr2 isoform IIIb regulates adrenal cortex development. Mol Cell Endocrinol. 2013a;371:182–8.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Finco I, LaPensee CR, Krill KT, Hammer GD. Hedgehog signaling and steroidogenesis. Annu Rev Physiol. 2015;77:105–29.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Drelon C, Berthon A, Mathieu M, Martinez A, Val P. Adrenal cortex tissue homeostasis and zonation: a WNT perspective. Mol Cell Endocrinol. 2015;408:156–64.PubMedCrossRefGoogle Scholar
  53. 53.
    Heikkila M, Peltoketo H, Leppaluoto J, Ilves M, Vuolteenaho O, Vainio S. Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology. 2002;143:4358–65.PubMedCrossRefGoogle Scholar
  54. 54.
    Vidal V, Sacco S, Rocha AS, da Silva F, Panzolini C, Dumontet T, Doan TM, Shan J, Rak-Raszewska A, Bird T, Vainio S, Martinez A, Schedl A. The adrenal capsule is a signaling center controlling cell renewal and zonation through Rspo3. Genes Dev. 2016;30:1389–94.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Burns MP, Rebeck GW. Intracellular cholesterol homeostasis and amyloid precursor protein processing. Biochim Biophys Acta. 2010;1801:853–9.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Horton JD, Goldstein JL, Brown MS. SREBPs: transcriptional mediators of lipid homeostasis. Cold Spring Harb Symp Quant Biol. 2002;67:491–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006;124:35–46.PubMedCrossRefGoogle Scholar
  58. 58.
    Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci U S A. 1999;96:11041–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Braamskamp MJ, Kusters DM, Wiegman A, Avis HJ, Wijburg FA, Kastelein JJ, van Trotsenburg AS, Hutten BA. Gonadal steroids, gonadotropins and DHEAS in young adults with familial hypercholesterolemia who had initiated statin therapy in childhood. Atherosclerosis. 2015;241:427–32.PubMedCrossRefGoogle Scholar
  60. 60.
    Laue L, Hoeg JM, Barnes K, Loriaux DL, Chrousos GP. The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway. J Clin Endocrinol Metab. 1987;64:531–5.PubMedCrossRefGoogle Scholar
  61. 61.
    Miller WL. Disorders in the initial steps of steroid hormone synthesis. J Steroid Biochem Mol Biol. 2016;165(Pt A):18–37.PubMedGoogle Scholar
  62. 62.
    Capponi AM. Regulation of cholesterol supply for mineralocorticoid biosynthesis. Trends Endocrinol Metab. 2002;13:118–21.PubMedCrossRefGoogle Scholar
  63. 63.
    Miller WL, Bose HS. Early steps in steroidogenesis: intracellular cholesterol trafficking. J Lipid Res. 2011;52:2111–35.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Burton BK, Balwani M, Feillet F, Baric I, Burrow TA, Camarena Grande C, Coker M, Consuelo-Sanchez A, Deegan P, Di Rocco M, Enns GM, Erbe R, Ezgu F, Ficicioglu C, Furuya KN, Kane J, Laukaitis C, Mengel E, Neilan EG, Nightingale S, Peters H, Scarpa M, Schwab KO, Smolka V, Valayannopoulos V, Wood M, Goodman Z, Yang Y, Eckert S, Rojas-Caro S, Quinn AG. A phase 3 trial of Sebelipase Alfa in Lysosomal acid lipase deficiency. N Engl J Med. 2015;373:1010–20.PubMedCrossRefGoogle Scholar
  65. 65.
    Peake KB, Vance JE. Defective cholesterol trafficking in Niemann-Pick C-deficient cells. FEBS Lett. 2010;584:2731–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis. 2015;38:187–99.PubMedCrossRefGoogle Scholar
  67. 67.
    Strauss JF 3rd, Kishida T, Christenson LK, Fujimoto T, Hiroi H. START domain proteins and the intracellular trafficking of cholesterol in steroidogenic cells. Mol Cell Endocrinol. 2003;202:59–65.PubMedCrossRefGoogle Scholar
  68. 68.
    Iyer LM, Koonin EV, Aravind L. Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily. Proteins. 2001;43:134–44.PubMedCrossRefGoogle Scholar
  69. 69.
    Alpy F, Stoeckel ME, Dierich A, Escola JM, Wendling C, Chenard MP, Vanier MT, Gruenberg J, Tomasetto C, Rio MC. The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein. J Biol Chem. 2001;276:4261–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Shen WJ, Azhar S, Kraemer FB. ACTH regulation of adrenal SR-B1. Front Endocrinol (Lausanne). 2016;7:42.Google Scholar
  71. 71.
    Rone MB, Fan J, Papadopoulos V. Cholesterol transport in steroid biosynthesis: role of protein-protein interactions and implications in disease states. Biochim Biophys Acta. 2009;1791:646–58.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Connelly MA, Kellner-Weibel G, Rothblat GH, Williams DL. SR-BI-directed HDL-cholesteryl ester hydrolysis. J Lipid Res. 2003;44:331–41.PubMedCrossRefGoogle Scholar
  73. 73.
    Kraemer FB, Shen WJ, Harada K, Patel S, Osuga J, Ishibashi S, Azhar S. Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis. Mol Endocrinol. 2004;18:549–57.PubMedCrossRefGoogle Scholar
  74. 74.
    Plump AS, Erickson SK, Weng W, Partin JS, Breslow JL, Williams DL. Apolipoprotein A-I is required for cholesteryl ester accumulation in steroidogenic cells and for normal adrenal steroid production. J Clin Invest. 1996;97:2660–71.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Taylor MJ, Sanjanwala AR, Morin EE, Rowland-Fisher E, Anderson K, Schwendeman A, Rainey WE. Synthetic high-density lipoprotein (sHDL) inhibits steroid production in HAC15 adrenal cells. Endocrinology. 2016;157:3122–9.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Cherradi N, Pardo B, Greenberg AS, Kraemer FB, Capponi AM. Angiotensin II activates cholesterol ester hydrolase in bovine adrenal glomerulosa cells through phosphorylation mediated by p42/p44 mitogen-activated protein kinase. Endocrinology. 2003;144:4905–15.PubMedCrossRefGoogle Scholar
  77. 77.
    Shen WJ, Patel S, Natu V, Hong R, Wang J, Azhar S, Kraemer FB. Interaction of hormone-sensitive lipase with steroidogenic acute regulatory protein: facilitation of cholesterol transfer in adrenal. J Biol Chem. 2003;278:43870–6.PubMedCrossRefGoogle Scholar
  78. 78.
    LaPensee CR, Mann JE, Rainey WE, Crudo V, Hunt SW 3rd, Hammer GD. ATR-101, a selective and potent inhibitor of acyl-CoA Acyltransferase 1, induces apoptosis in H295R adrenocortical cells and in the adrenal cortex of dogs. Endocrinology. 2016;157:1775–88.PubMedCrossRefGoogle Scholar
  79. 79.
    Sbiera S, Leich E, Liebisch G, Sbiera I, Schirbel A, Wiemer L, Matysik S, Eckhardt C, Gardill F, Gehl A, Kendl S, Weigand I, Bala M, Ronchi CL, Deutschbein T, Schmitz G, Rosenwald A, Allolio B, Fassnacht M, Kroiss M. Mitotane inhibits sterol-O-acyl Transferase 1 triggering lipid-mediated endoplasmic reticulum stress and apoptosis in adrenocortical carcinoma cells. Endocrinology. 2015;156:3895–908.PubMedCrossRefGoogle Scholar
  80. 80.
    Scheidt HA, Haralampiev I, Theisgen S, Schirbel A, Sbiera S, Huster D, Kroiss M, Muller P. The adrenal specific toxicant mitotane directly interacts with lipid membranes and alters membrane properties depending on lipid composition. Mol Cell Endocrinol. 2016;428:68–81.PubMedCrossRefGoogle Scholar
  81. 81.
    Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 1999;13:1211–33.PubMedCrossRefGoogle Scholar
  82. 82.
    Crivello JF, Jefcoate CR. Intracellular movement of cholesterol in rat adrenal cells. Kinetics and effects of inhibitors. J Biol Chem. 1980;255:8144–51.PubMedGoogle Scholar
  83. 83.
    Privalle CT, Crivello JF, Jefcoate CR. Regulation of intramitochondrial cholesterol transfer to side-chain cleavage cytochrome P-450 in rat adrenal gland. Proc Natl Acad Sci U S A. 1983;80:702–6.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Hall PF, Almahbobi G. Roles of microfilaments and intermediate filaments in adrenal steroidogenesis. Microsc Res Tech. 1997;36:463–79.PubMedCrossRefGoogle Scholar
  85. 85.
    Li D, Sewer MB. RhoA and DIAPH1 mediate adrenocorticotropin-stimulated cortisol biosynthesis by regulating mitochondrial trafficking. Endocrinology. 2010;151:4313–23.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Sewer MB, Li D. Regulation of steroid hormone biosynthesis by the cytoskeleton. Lipids. 2008;43:1109–15.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Arbuzova A, Schmitz AA, Vergeres G. Cross-talk unfolded: MARCKS proteins. Biochem J. 2002;362:1–12.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Betancourt-Calle S, Bollag WB, Jung EM, Calle RA, Rasmussen H. Effects of angiotensin II and adrenocorticotropic hormone on myristoylated alanine-rich C-kinase substrate phosphorylation in glomerulosa cells. Mol Cell Endocrinol. 1999;154:1–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Kraemer FB, Khor VK, Shen WJ, Azhar S. Cholesterol ester droplets and steroidogenesis. Mol Cell Endocrinol. 2013;371:15–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Barbosa AD, Savage DB, Siniossoglou S. Lipid droplet-organelle interactions: emerging roles in lipid metabolism. Curr Opin Cell Biol. 2015;35:91–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Lin Y, Hou X, Shen WJ, Hanssen R, Khor VK, Cortez Y, Roseman AN, Azhar S, Kraemer FB. SNARE-mediated cholesterol movement to mitochondria supports Steroidogenesis in rodent cells. Mol Endocrinol. 2016;30:234–47.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Jagerstrom S, Polesie S, Wickstrom Y, Johansson BR, Schroder HD, Hojlund K, Bostrom P. Lipid droplets interact with mitochondria using SNAP23. Cell Biol Int. 2009;33:934–40.PubMedCrossRefGoogle Scholar
  93. 93.
    Enrich C, Rentero C, Hierro A, Grewal T. Role of cholesterol in SNARE-mediated trafficking on intracellular membranes. J Cell Sci. 2015;128:1071–81.PubMedCrossRefGoogle Scholar
  94. 94.
    Kraemer FB, Shen WJ, Azhar S. SNAREs and cholesterol movement for steroidogenesis. Mol Cell: Endocrinol; 2016.Google Scholar
  95. 95.
    Midzak A, Papadopoulos V. Adrenal mitochondria and Steroidogenesis: from individual proteins to functional protein assemblies. Front Endocrinol (Lausanne). 2016;7:106.Google Scholar
  96. 96.
    Prasad M, Kaur J, Pawlak KJ, Bose M, Whittal RM, Bose HS. Mitochondria-associated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)-voltage-dependent anion channel 2 (VDAC2) interaction. J Biol Chem. 2015;290:2604–16.PubMedCrossRefGoogle Scholar
  97. 97.
    Doghman-Bouguerra M, Lalli E. The ER-mitochondria couple: in life and death from steroidogenesis to tumorigenesis. Mol Cell Endocrinol. 2016;441:176–84.PubMedCrossRefGoogle Scholar
  98. 98.
    Vance JE. MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim Biophys Acta. 2014;1841:595–609.PubMedCrossRefGoogle Scholar
  99. 99.
    Doghman-Bouguerra M, Granatiero V, Sbiera S, Sbiera I, Lacas-Gervais S, Brau F, Fassnacht M, Rizzuto R, Lalli E. FATE1 antagonizes calcium- and drug-induced apoptosis by uncoupling ER and mitochondria. EMBO Rep. 2016;17(9):1264–80.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Hayashi T, Su TP. Sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther. 2003;306:718–25.PubMedCrossRefGoogle Scholar
  101. 101.
    Marriott KS, Prasad M, Thapliyal V, Bose HS. Sigma-1 receptor at the mitochondrial-associated endoplasmic reticulum membrane is responsible for mitochondrial metabolic regulation. J Pharmacol Exp Ther. 2012;343:578–86.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Jinn S, Brandis KA, Ren A, Chacko A, Dudley-Rucker N, Gale SE, Sidhu R, Fujiwara H, Jiang H, Olsen BN, Schaffer JE, Ory DS. snoRNA U17 regulates cellular cholesterol trafficking. Cell Metab. 2015;21:855–67.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Ferguson JJ Jr. Protein synthesis and Adrenocorticotropin responsiveness. J Biol Chem. 1963;238:2754–9.PubMedGoogle Scholar
  104. 104.
    Garren LD, Ney RL, Davis WW. Studies on the role of protein synthesis in the regulation of corticosterone production by adrenocorticotropic hormone in vivo. Proc Natl Acad Sci U S A. 1965;53:1443–50.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Clark BJ, Wells J, King SR, Stocco DM. The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem. 1994;269:28314–22.PubMedGoogle Scholar
  106. 106.
    Miller WL. Mechanism of StAR's regulation of mitochondrial cholesterol import. Mol Cell Endocrinol. 2007a;265-266:46–50.PubMedCrossRefGoogle Scholar
  107. 107.
    Duarte A, Castillo AF, Podesta EJ, Poderoso C. Mitochondrial fusion and ERK activity regulate steroidogenic acute regulatory protein localization in mitochondria. PLoS One. 2014;9:e100387.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Manna PR, Dyson MT, Stocco DM. Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives. Mol Hum Reprod. 2009;15:321–33.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Pon LA, Hartigan JA, Orme-Johnson NR. Acute ACTH regulation of adrenal corticosteroid biosynthesis. Rapid accumulation of a phosphoprotein. J Biol Chem. 1986;261:13309–16.PubMedGoogle Scholar
  110. 110.
    Pon LA, Orme-Johnson NR. Acute stimulation of corpus luteum cells by gonadotrophin or adenosine 3′,5′-monophosphate causes accumulation of a phosphoprotein concurrent with acceleration of steroid synthesis. Endocrinology. 1988;123:1942–8.PubMedCrossRefGoogle Scholar
  111. 111.
    Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, Strauss JF 3rd. Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. J Biol Chem. 1997;272:32656–62.PubMedCrossRefGoogle Scholar
  112. 112.
    Manna PR, Wang XJ, Stocco DM. Involvement of multiple transcription factors in the regulation of steroidogenic acute regulatory protein gene expression. Steroids. 2003;68:1125–34.PubMedCrossRefGoogle Scholar
  113. 113.
    Tremblay JJ, Viger RS. Novel roles for GATA transcription factors in the regulation of steroidogenesis. J Steroid Biochem Mol Biol. 2003;85:291–8.PubMedCrossRefGoogle Scholar
  114. 114.
    Cummins CL, Volle DH, Zhang Y, McDonald JG, Sion B, Lefrancois-Martinez AM, Caira F, Veyssiere G, Mangelsdorf DJ, Lobaccaro JM. Liver X receptors regulate adrenal cholesterol balance. J Clin Invest. 2006;116:1902–12.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Manna PR, Cohen-Tannoudji J, Counis R, Garner CW, Huhtaniemi I, Kraemer FB, Stocco DM. Mechanisms of action of hormone-sensitive lipase in mouse Leydig cells: its role in the regulation of the steroidogenic acute regulatory protein. J Biol Chem. 2013;288:8505–18.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Arakane F, Sugawara T, Nishino H, Liu Z, Holt JA, Pain D, Stocco DM, Miller WL, Strauss JF 3rd. Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action. Proc Natl Acad Sci U S A. 1996;93:13731–6.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Bose HS, Whittal RM, Baldwin MA, Miller WL. The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule. Proc Natl Acad Sci U S A. 1999;96:7250–5.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Artemenko IP, Zhao D, Hales DB, Hales KH, Jefcoate CR. Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells. J Biol Chem. 2001;276:46583–96.PubMedCrossRefGoogle Scholar
  119. 119.
    Bahat A, Perlberg S, Melamed-Book N, Lauria I, Langer T, Orly J. StAR enhances transcription of genes encoding the mitochondrial proteases involved in its own degradation. Mol Endocrinol. 2014;28:208–24.PubMedCrossRefGoogle Scholar
  120. 120.
    Bose HS, Sugawara T, Strauss JF 3rd, Miller WL. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med. 1996;335:1870–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Lin D, Sugawara T, Strauss JF 3rd, Clark BJ, Stocco DM, Saenger P, Rogol A, Miller WL. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science. 1995;267:1828–31.PubMedCrossRefGoogle Scholar
  122. 122.
    Caron KM, Soo SC, Wetsel WC, Stocco DM, Clark BJ, Parker KL. Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci U S A. 1997;94:11540–5.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Hasegawa T, Zhao L, Caron KM, Majdic G, Suzuki T, Shizawa S, Sasano H, Parker KL. Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. Mol Endocrinol. 2000;14:1462–71.PubMedCrossRefGoogle Scholar
  124. 124.
    Sasaki G, Ishii T, Jeyasuria P, Jo Y, Bahat A, Orly J, Hasegawa T, Parker KL. Complex role of the mitochondrial targeting signal in the function of steroidogenic acute regulatory protein revealed by bacterial artificial chromosome transgenesis in vivo. Mol Endocrinol. 2008;22:951–64.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Rone MB, Midzak AS, Issop L, Rammouz G, Jagannathan S, Fan J, Ye X, Blonder J, Veenstra T, Papadopoulos V. Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones. Mol Endocrinol. 2012;26:1868–82.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Papadopoulos V, Miller WL. Role of mitochondria in steroidogenesis. Best Pract Res Clin Endocrinol Metab. 2012;26:771–90.PubMedCrossRefGoogle Scholar
  127. 127.
    Shoshan-Barmatz V, Keinan N, Zaid H. Uncovering the role of VDAC in the regulation of cell life and death. J Bioenerg Biomembr. 2008;40:183–91.PubMedCrossRefGoogle Scholar
  128. 128.
    Bose M, Whittal RM, Miller WL, Bose HS. Steroidogenic activity of StAR requires contact with mitochondrial VDAC1 and phosphate carrier protein. J Biol Chem. 2008;283:8837–45.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Selvaraj V, Stocco DM. The changing landscape in translocator protein (TSPO) function. Trends Endocrinol Metab. 2015;26:341–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Krueger KE, Papadopoulos V. Peripheral-type benzodiazepine receptors mediate translocation of cholesterol from outer to inner mitochondrial membranes in adrenocortical cells. J Biol Chem. 1990;265:15015–22.PubMedGoogle Scholar
  131. 131.
    Lacapere JJ, Delavoie F, Li H, Peranzi G, Maccario J, Papadopoulos V, Vidic B. Structural and functional study of reconstituted peripheral benzodiazepine receptor. Biochem Biophys Res Commun. 2001;284:536–41.PubMedCrossRefGoogle Scholar
  132. 132.
    Li H, Yao Z, Degenhardt B, Teper G, Papadopoulos V. Cholesterol binding at the cholesterol recognition/interaction amino acid consensus (CRAC) of the peripheral-type benzodiazepine receptor and inhibition of steroidogenesis by an HIV TAT-CRAC peptide. Proc Natl Acad Sci U S A. 2001b;98:1267–72.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    West LA, Horvat RD, Roess DA, Barisas BG, Juengel JL, Niswender GD. Steroidogenic acute regulatory protein and peripheral-type benzodiazepine receptor associate at the mitochondrial membrane. Endocrinology. 2001;142:502–5.PubMedCrossRefGoogle Scholar
  134. 134.
    Papadopoulos V, Aghazadeh Y, Fan J, Campioli E, Zirkin B, Midzak A. Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis. Mol Cell Endocrinol. 2015;408:90–8.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Selvaraj V, Stocco DM, Tu LN. Minireview: translocator protein (TSPO) and steroidogenesis: a reappraisal. Mol Endocrinol. 2015;29:490–501.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Selvaraj V, Tu LN, Stocco DM. Crucial role reported for TSPO in viability and Steroidogenesis is a misconception. Commentary: Conditional Steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation. Front Endocrinol (Lausanne). 2016;7:91.Google Scholar
  137. 137.
    Banati RB, Middleton RJ, Chan R, Hatty CR, Kam WW, Quin C, Graeber MB, Parmar A, Zahra D, Callaghan P, Fok S, Howell NR, Gregoire M, Szabo A, Pham T, Davis E, Liu GJ. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun. 2014;5:5452.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Fan J, Campioli E, Midzak A, Culty M, Papadopoulos V. 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;112:7261–6.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Tu LN, Morohaku K, Manna PR, Pelton SH, Butler WR, Stocco DM, Selvaraj V. Peripheral benzodiazepine receptor/translocator protein global knock-out mice are viable with no effects on steroid hormone biosynthesis. J Biol Chem. 2014;289:27444–54.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Tu LN, Zhao AH, Stocco DM, Selvaraj V. PK11195 effect on steroidogenesis is not mediated through the translocator protein (TSPO). Endocrinology. 2015;156:1033–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Tu LN, Zhao AH, Hussein M, Stocco DM, Selvaraj V. Translocator protein (TSPO) affects Mitochondrial fatty acid oxidation in Steroidogenic cells. Endocrinology. 2016;157:1110–21.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Li H, Degenhardt B, Tobin D, Yao ZX, Tasken K, Papadopoulos V. Identification, localization, and function in steroidogenesis of PAP7: a peripheral-type benzodiazepine receptor- and PKA (RIalpha)-associated protein. Mol Endocrinol. 2001a;15:2211–28.PubMedGoogle Scholar
  143. 143.
    Liu J, Rone MB, Papadopoulos V. Protein-protein interactions mediate mitochondrial cholesterol transport and steroid biosynthesis. J Biol Chem. 2006;281:38879–93.PubMedCrossRefGoogle Scholar
  144. 144.
    Poderoso C, Maloberti P, Duarte A, Neuman I, Paz C, Cornejo Maciel F, Podesta EJ. Hormonal activation of a kinase cascade localized at the mitochondria is required for StAR protein activity. Mol Cell Endocrinol. 2009;300:37–42.PubMedCrossRefGoogle Scholar
  145. 145.
    Carrasco GA, Van de Kar LD. Neuroendocrine pharmacology of stress. Eur J Pharmacol. 2003;463:235–72.PubMedCrossRefGoogle Scholar
  146. 146.
    Habib KE, Gold PW, Chrousos GP. Neuroendocrinology of stress. Endocrinol Metab Clin N Am. 2001;30:695–728.CrossRefGoogle Scholar
  147. 147.
    Itoi K, Seasholtz AF, Watson SJ. Cellular and extracellular regulatory mechanisms of hypothalamic corticotropin-releasing hormone neurons. Endocr J. 1998;45:13–33.PubMedCrossRefGoogle Scholar
  148. 148.
    Clark AJ. 60 YEARS OF POMC: the proopiomelanocortin gene: discovery, deletion and disease. J Mol Endocrinol. 2015;56(4):T27–37.PubMedCrossRefGoogle Scholar
  149. 149.
    Raffin-Sanson ML, de Keyzer Y, Bertagna X. Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Eur J Endocrinol. 2003;149:79–90.PubMedCrossRefGoogle Scholar
  150. 150.
    Ruggiero C, Lalli E. Impact of ACTH Signaling on transcriptional regulation of Steroidogenic genes. Front Endocrinol (Lausanne). 2016;7:24.Google Scholar
  151. 151.
    Richards EM, Hua Y, Keller-Wood M. Pharmacology and physiology of ovine corticosteroid receptors. Neuroendocrinology. 2003;77:2–14.PubMedCrossRefGoogle Scholar
  152. 152.
    Gomez-Sanchez EP. Brain mineralocorticoid receptors in cognition and cardiovascular homeostasis. Steroids. 2014b;91:20–31.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Gallo-Payet N, Battista MC. Steroidogenesis-adrenal cell signal transduction. Compr Physiol. 2014;4:889–964.PubMedCrossRefGoogle Scholar
  154. 154.
    Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 2010;72:517–49.PubMedCrossRefGoogle Scholar
  155. 155.
    Kiessling S, Eichele G, Oster H. Adrenal glucocorticoids have a key role in circadian resynchronization in a mouse model of jet lag. J Clin Invest. 2010;120:2600–9.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Ota T, Fustin JM, Yamada H, Doi M, Okamura H. Circadian clock signals in the adrenal cortex. Mol Cell Endocrinol. 2012;349:30–7.PubMedCrossRefGoogle Scholar
  157. 157.
    Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res. 1972;42:201–6.PubMedCrossRefGoogle Scholar
  158. 158.
    Park SY, Walker JJ, Johnson NW, Zhao Z, Lightman SL, Spiga F. Constant light disrupts the circadian rhythm of steroidogenic proteins in the rat adrenal gland. Mol Cell Endocrinol. 2013;371:114–23.PubMedCrossRefGoogle Scholar
  159. 159.
    Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk C, Reichardt HM, Schutz G, Schibler U. Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science. 2000;289:2344–7.PubMedCrossRefGoogle Scholar
  160. 160.
    Barclay JL, Shostak A, Leliavski A, Tsang AH, Johren O, Muller-Fielitz H, Landgraf D, Naujokat N, van der Horst GT, Oster H. High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in cry-deficient mice. Am J Physiol Endocrinol Metab. 2013;304:E1053–63.PubMedCrossRefGoogle Scholar
  161. 161.
    Lamia KA, Papp SJ, Yu RT, Barish GD, Uhlenhaut NH, Jonker JW, Downes M, Evans RM. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature. 2011;480:552–6.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Leliavski A, Shostak A, Husse J, Oster H. Impaired glucocorticoid production and response to stress in Arntl-deficient male mice. Endocrinology. 2014;155:133–42.PubMedCrossRefGoogle Scholar
  163. 163.
    Oster H, Damerow S, Hut RA, Eichele G. Transcriptional profiling in the adrenal gland reveals circadian regulation of hormone biosynthesis genes and nucleosome assembly genes. J Biol Rhythm. 2006;21:350–61.CrossRefGoogle Scholar
  164. 164.
    Son GH, Chung S, Choe HK, Kim HD, Baik SM, Lee H, Lee HW, Choi S, Sun W, Kim H, Cho S, Lee KH, Kim K. Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production. Proc Natl Acad Sci U S A. 2008;105:20970–5.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J. Obesity and metabolic syndrome in circadian clock mutant mice. Science. 2005;308:1043–5.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Guran T, Buonocore F, Saka N, Ozbek MN, Aycan Z, Bereket A, Bas F, Darcan S, Bideci A, Guven A, Demir K, Akinci A, Buyukinan M, Aydin BK, Turan S, Agladioglu SY, Atay Z, Abali ZY, Tarim O, Catli G, Yuksel B, Akcay T, Yildiz M, Ozen S, Doger E, Demirbilek H, Ucar A, Isik E, Ozhan B, Bolu S, Ozgen IT, Suntharalingham JP, Achermann JC. Rare causes of primary adrenal insufficiency: genetic and clinical characterization of a large Nationwide cohort. J Clin Endocrinol Metab. 2016;101:284–92.PubMedCrossRefGoogle Scholar
  167. 167.
    de Joussineau C, Sahut-Barnola I, Levy I, Saloustros E, Val P, Stratakis CA, Martinez A. The cAMP pathway and the control of adrenocortical development and growth. Mol Cell Endocrinol. 2012;351:28–36.PubMedCrossRefGoogle Scholar
  168. 168.
    Sahut-Barnola I, de Joussineau C, Val P, Lambert-Langlais S, Damon C, Lefrancois-Martinez AM, Pointud JC, Marceau G, Sapin V, Tissier F, Ragazzon B, Bertherat J, Kirschner LS, Stratakis CA, Martinez A. Cushing's syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. PLoS Genet. 2010;6:e1000980.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    de Joussineau C, Sahut-Barnola I, Tissier F, Dumontet T, Drelon C, Batisse-Lignier M, Tauveron I, Pointud JC, Lefrancois-Martinez AM, Stratakis CA, Bertherat J, Val P, Martinez A. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD). Hum Mol: Genet; 2014.Google Scholar
  170. 170.
    Beuschlein F, Fassnacht M, Assie G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med. 2014;370:1019–28.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Ronchi CL, Di Dalmazi G, Faillot S, Sbiera S, Assie G, Weigand I, Calebiro D, Schwarzmayr T, Appenzeller S, Rubin B, Waldmann J, Scaroni C, Bartsch DK, Mantero F, Mannelli M, Kastelan D, Chiodini I, Bertherat J, Reincke M, Strom TM, Fassnacht M, Beuschlein F. Genetic landscape of sporadic unilateral adrenocortical adenomas without PRKACA p.Leu206Arg mutation. J Clin Endocrinol Metab. 2016;101(9):3526–38.PubMedCrossRefGoogle Scholar
  172. 172.
    Aumo L, Rusten M, Mellgren G, Bakke M, Lewis AE. Functional roles of protein kinase a (PKA) and exchange protein directly activated by 3′,5′-cyclic adenosine 5′-monophosphate (cAMP) 2 (EPAC2) in cAMP-mediated actions in adrenocortical cells. Endocrinology. 2010;151:2151–61.PubMedCrossRefGoogle Scholar
  173. 173.
    Lewis AE, Aesoy R, Bakke M. Role of EPAC in cAMP-mediated actions in adrenocortical cells. Front Endocrinol (Lausanne). 2016;7:63.Google Scholar
  174. 174.
    Bos JL. Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci. 2006;31:680–6.PubMedCrossRefGoogle Scholar
  175. 175.
    Enyeart JA, Enyeart JJ. Metabolites of an Epac-selective cAMP analog induce cortisol synthesis by adrenocortical cells through a cAMP-independent pathway. PLoS One. 2009;4:e6088.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Horvath A, Stratakis CA. Unraveling the molecular basis of micronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2008;15:227–33.PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Azevedo MF, Faucz FR, Bimpaki E, Horvath A, Levy I, de Alexandre RB, Ahmad F, Manganiello V, Stratakis CA. Clinical and molecular genetics of the phosphodiesterases (PDEs). Endocr Rev. 2014;35:195–233.PubMedCrossRefGoogle Scholar
  178. 178.
    Horvath A, Giatzakis C, Tsang K, Greene E, Osorio P, Boikos S, Libe R, Patronas Y, Robinson-White A, Remmers E, Bertherat J, Nesterova M, Stratakis CA. A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. Eur J Hum Genet. 2008;16(10):1245–53.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Abdou HS, Bergeron F, Tremblay JJ. A cell-autonomous molecular cascade initiated by AMP-activated protein kinase represses steroidogenesis. Mol Cell Biol. 2014;34:4257–71.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Tremblay JJ. Molecular regulation of steroidogenesis in endocrine Leydig cells. Steroids. 2015;103:3–10.PubMedCrossRefGoogle Scholar
  181. 181.
    Dada L, Cornejo Maciel F, Neuman I, Mele PG, Maloberti P, Paz C, Cymeryng C, Finkielstein C, Mendez CF, Podesta EJ. Cytosolic and mitochondrial proteins as possible targets of cycloheximide effect on adrenal steroidogenesis. Endocr Res. 1996;22:533–9.PubMedCrossRefGoogle Scholar
  182. 182.
    Wang X, Walsh LP, Reinhart AJ, Stocco DM. The role of arachidonic acid in steroidogenesis and steroidogenic acute regulatory (StAR) gene and protein expression. J Biol Chem. 2000;275:20204–9.PubMedCrossRefGoogle Scholar
  183. 183.
    Kang MJ, Fujino T, Sasano H, Minekura H, Yabuki N, Nagura H, Iijima H, Yamamoto TT. A novel arachidonate-preferring acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal, ovary, and testis. Proc Natl Acad Sci U S A. 1997;94:2880–4.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Lewin TM, Van Horn CG, Krisans SK, Coleman RA. Rat liver acyl-CoA synthetase 4 is a peripheral-membrane protein located in two distinct subcellular organelles, peroxisomes, and mitochondrial-associated membrane. Arch Biochem Biophys. 2002;404:263–70.PubMedCrossRefGoogle Scholar
  185. 185.
    Wilson DB, Prescott SM, Majerus PW. Discovery of an arachidonoyl coenzyme a synthetase in human platelets. J Biol Chem. 1982;257:3510–5.PubMedGoogle Scholar
  186. 186.
    Soupene E, Kuypers FA. Mammalian long-chain acyl-CoA synthetases. Exp Biol Med (Maywood). 2008;233:507–21.CrossRefGoogle Scholar
  187. 187.
    Cornejo Maciel F, Maloberti P, Neuman I, Cano F, Castilla R, Castillo F, Paz C, Podesta EJ. An arachidonic acid-preferring acyl-CoA synthetase is a hormone-dependent and obligatory protein in the signal transduction pathway of steroidogenic hormones. J Mol Endocrinol. 2005;34:655–66.PubMedCrossRefGoogle Scholar
  188. 188.
    Maloberti P, Castilla R, Castillo F, Cornejo Maciel F, Mendez CF, Paz C, Podesta EJ. Silencing the expression of mitochondrial acyl-CoA thioesterase I and acyl-CoA synthetase 4 inhibits hormone-induced steroidogenesis. FEBS J. 2005;272:1804–14.PubMedCrossRefGoogle Scholar
  189. 189.
    Cooke M, Mele P, Maloberti P, Duarte A, Poderoso C, Orlando U, Paz C, Cornejo Maciel F, Podesta EJ. Tyrosine phosphatases as key regulators of StAR induction and cholesterol transport: SHP2 as a potential tyrosine phosphatase involved in steroid synthesis. Mol Cell Endocrinol. 2011;336:63–9.PubMedCrossRefGoogle Scholar
  190. 190.
    Paz C, Cornejo Maciel F, Gorostizaga A, Castillo AF, Mori Sequeiros Garcia MM, Maloberti PM, Orlando UD, Mele PG, Poderoso C, Podesta EJ. Role of protein phosphorylation and tyrosine phosphatases in the adrenal regulation of steroid synthesis and Mitochondrial function. Front Endocrinol (Lausanne). 2016;7:60.Google Scholar
  191. 191.
    Houslay MD, Kolch W. Cell-type specific integration of cross-talk between extracellular signal-regulated kinase and cAMP signaling. Mol Pharmacol. 2000;58:659–68.PubMedCrossRefGoogle Scholar
  192. 192.
    Lefrancois-Martinez AM, Blondet-Trichard A, Binart N, Val P, Chambon C, Sahut-Barnola I, Pointud JC, Martinez A. Transcriptional control of adrenal steroidogenesis: novel connection between Janus kinase (JAK) 2 protein and protein kinase a (PKA) through stabilization of cAMP response element-binding protein (CREB) transcription factor. J Biol Chem. 2011;286:32976–85.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Bornstein SR, Engeland WC, Ehrhart-Bornstein M, Herman JP. Dissociation of ACTH and glucocorticoids. Trends Endocrinol Metab. 2008;19:175–80.PubMedCrossRefGoogle Scholar
  194. 194.
    Ansurudeen I, Willenberg HS, Kopprasch S, Krug AW, Ehrhart-Bornstein M, Bornstein SR. Endothelial factors mediate aldosterone release via PKA-independent pathways. Mol Cell Endocrinol. 2009;300:66–70.PubMedCrossRefGoogle Scholar
  195. 195.
    Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, Langenbach J, Willenberg HS, Barthel A, Hauner H, McCann SM, Scherbaum WA, Bornstein SR. Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci U S A. 2003;100:14211–6.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Spät A, Hunyady L, Szanda G. Signaling interactions in the adrenal cortex. Front Endocrinol (Lausanne). 2016;7:17.Google Scholar
  197. 197.
    Nogueira EF, Bollag WB, Rainey WE. Angiotensin II regulation of adrenocortical gene transcription. Mol Cell Endocrinol. 2009;302:230–6.PubMedCrossRefGoogle Scholar
  198. 198.
    Clark BJ, Combs R. Angiotensin II and cyclic adenosine 3′,5′-monophosphate induce human steroidogenic acute regulatory protein transcription through a common steroidogenic factor-1 element. Endocrinology. 1999;140:4390–8.PubMedCrossRefGoogle Scholar
  199. 199.
    Zennaro MC, Boulkroun S, Fernandes-Rosa F. An update on novel mechanisms of primary aldosteronism. J Endocrinol. 2015;224:R63–77.PubMedCrossRefGoogle Scholar
  200. 200.
    Vaidya A, Hamrahian A, Auchus RJ. Genetics of primary Aldosteronism. Endocr Pract. 2015;21(5):1–15.Google Scholar
  201. 201.
    Spät A. Glomerulosa cell--a unique sensor of extracellular K+ concentration. Mol Cell Endocrinol. 2004;217:23–6.PubMedCrossRefGoogle Scholar
  202. 202.
    Himathongkam T, Dluhy RG, Williams GH. Potassim-aldosterone-renin interrelationships. J Clin Endocrinol Metab. 1975;41:153–9.PubMedCrossRefGoogle Scholar
  203. 203.
    Rege J, Nakamura Y, Satoh F, Morimoto R, Kennedy MR, Layman LC, Honma S, Sasano H, Rainey WE. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab. 2013;98:1182–8.PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Udhane SS, Flück CE. Regulation of human (adrenal) androgen biosynthesis-new insights from novel throughput technology studies. Biochem Pharmacol. 2016;102:20–33.PubMedCrossRefGoogle Scholar
  205. 205.
    Kirschner MA, Bardin CW. Androgen production and metabolism in normal and virilized women. Metabolism. 1972;21:667–88.PubMedCrossRefGoogle Scholar
  206. 206.
    Ferraldeschi R, Sharifi N, Auchus RJ, Attard G. Molecular pathways: inhibiting steroid biosynthesis in prostate cancer. Clin Cancer Res. 2013;19:3353–9.PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Turcu AF, Nanba AT, Chomic R, Upadhyay SK, Giordano T, Shields JJ, Merke DP, Rainey W, Auchus R. Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency. Eur J Endocrinol. 2016;174(5):601–9.PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA. The regulation of steroid action by Sulfation and Desulfation. Endocr Rev. 2015;36:526–63.PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N, Smeitink JA, Smeets R, Sweep FC, Claahsen-van der Grinten HL, Arlt W. Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med. 2009;360:2310–8.PubMedCrossRefGoogle Scholar
  210. 210.
    Migeon CJ, Keller AR, Lawrence B, Shepard TH 2nd. Dehydroepiandrosterone and androsterone levels in human plasma: effect of age and sex; day-to-day and diurnal variations. J Clin Endocrinol Metab. 1957;17:1051–62.PubMedCrossRefGoogle Scholar
  211. 211.
    Brett EM, Auchus RJ. Genetic forms of adrenal insufficiency. Endocr Pract. 2015;1-17Google Scholar
  212. 212.
    Pandey AV, Mellon SH, Miller WL. Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17. J Biol Chem. 2003;278:2837–44.PubMedCrossRefGoogle Scholar
  213. 213.
    Tee MK, Miller WL. Phosphorylation of human cytochrome P450c17 by p38alpha selectively increases 17,20 lyase activity and androgen biosynthesis. J Biol Chem. 2013;288:23903–13.PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Miller WL, Tee MK. The post-translational regulation of 17,20 lyase activity. Mol Cell Endocrinol. 2015;408:99–106.PubMedCrossRefGoogle Scholar
  215. 215.
    Rege J, Nishimoto HK, Nishimoto K, Rodgers RJ, Auchus RJ, Rainey WE. Bone morphogenetic protein-4 (BMP4): a paracrine regulator of human adrenal C19 steroid synthesis. Endocrinology. 2015;156:2530–40.PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Kempna P, Marti N, Udhane S, Flück CE. Regulation of androgen biosynthesis - a short review and preliminary results from the hyperandrogenic starvation NCI-H295R cell model. Mol Cell Endocrinol. 2015;408:124–32.PubMedCrossRefGoogle Scholar
  217. 217.
    Baba T, Otake H, Sato T, Miyabayashi K, Shishido Y, Wang CY, Shima Y, Kimura H, Yagi M, Ishihara Y, Hino S, Ogawa H, Nakao M, Yamazaki T, Kang D, Ohkawa Y, Suyama M, Chung BC, Morohashi K. Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1. Nat Commun. 2014;5:3634.PubMedCrossRefGoogle Scholar
  218. 218.
    Ruggiero C, Doghman M, Lalli E. How genomic studies have improved our understanding of the mechanisms of transcriptional regulation by NR5A nuclear receptors. Mol Cell Endocrinol. 2014;408:138–44.PubMedCrossRefGoogle Scholar
  219. 219.
    Crawford PA, Sadovsky Y, Milbrandt J. Nuclear receptor steroidogenic factor 1 directs embryonic stem cells toward the steroidogenic lineage. Mol Cell Biol. 1997;17:3997–4006.PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Mizutani T, Kawabe S, Ishikane S, Imamichi Y, Umezawa A, Miyamoto K. Identification of novel steroidogenic factor 1 (SF-1)-target genes and components of the SF-1 nuclear complex. Mol Cell Endocrinol. 2015;408:133–7.PubMedCrossRefGoogle Scholar
  221. 221.
    Urs AN, Dammer E, Kelly S, Wang E, Merrill AH Jr, Sewer MB. Steroidogenic factor-1 is a sphingolipid binding protein. Mol Cell Endocrinol. 2007;265-266:174–8.PubMedCrossRefGoogle Scholar
  222. 222.
    Blind RD, Suzawa M, Ingraham HA. Direct modification and activation of a nuclear receptor-PIP2 complex by the inositol lipid kinase IPMK. Sci Signal. 2012;5:ra44.PubMedPubMedCentralCrossRefGoogle Scholar
  223. 223.
    Doghman M, Karpova T, Rodrigues GA, Arhatte M, De MJ, Cavalli LR, Virolle V, Barbry P, Zambetti GP, Figueiredo BC, Heckert LL, Lalli E. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol Endocrinol. 2007;21:2968–87.PubMedCrossRefGoogle Scholar
  224. 224.
    Figueiredo BC, Cavalli LR, Pianovski MA, Lalli E, Sandrini R, Ribeiro RC, Zambetti G, DeLacerda L, Rodrigues GA, Haddad BR. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J Clin Endocrinol Metab. 2005;90:615–9.PubMedCrossRefGoogle Scholar
  225. 225.
    Lee FY, Faivre EJ, Suzawa M, Lontok E, Ebert D, Cai F, Belsham DD, Ingraham HA. Eliminating SF-1 (NR5A1) sumoylation in vivo results in ectopic hedgehog signaling and disruption of endocrine development. Dev Cell. 2011;21:315–27.PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Parker KL. The roles of steroidogenic factor 1 in endocrine development and function. Mol Cell Endocrinol. 1998;145:15–20.PubMedCrossRefGoogle Scholar
  227. 227.
    Lalli E, Melner MH, Stocco DM, Sassone-Corsi P. DAX-1 blocks steroid production at multiple levels. Endocrinology. 1998;139:4237–43.PubMedCrossRefGoogle Scholar
  228. 228.
    Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol. 2001;185:17–25.PubMedCrossRefGoogle Scholar
  229. 229.
    Scheys JO, Heaton JH, Hammer GD. Evidence of adrenal failure in aging Dax1-deficient mice. Endocrinology. 2011;152:3430–9.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015;29:607–19.PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P. DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis. Nature. 1997;390:311–5.PubMedCrossRefGoogle Scholar
  232. 232.
    Sands WA, Palmer TM. Regulating gene transcription in response to cyclic AMP elevation. Cell Signal. 2008;20:460–6.PubMedCrossRefGoogle Scholar
  233. 233.
    Gau D, Lemberger T, von Gall C, Kretz O, Le Minh N, Gass P, Schmid W, Schibler U, Korf HW, Schutz G. Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock. Neuron. 2002;34:245–53.PubMedCrossRefGoogle Scholar
  234. 234.
    Jimenez P, Saner K, Mayhew B, Rainey WE. GATA-6 is expressed in the human adrenal and regulates transcription of genes required for adrenal androgen biosynthesis. Endocrinology. 2003;144:4285–8.PubMedCrossRefGoogle Scholar
  235. 235.
    Kiiveri S, Liu J, Westerholm-Ormio M, Narita N, Wilson DB, Voutilainen R, Heikinheimo M. Differential expression of GATA-4 and GATA-6 in fetal and adult mouse and human adrenal tissue. Endocrinology. 2002;143:3136–43.PubMedCrossRefGoogle Scholar
  236. 236.
    Nakamura Y, Suzuki T, Sasano H. Transcription factor GATA-6 in the human adrenocortex: association with adrenal development and aging. Endocr J. 2007;54:783–9.PubMedCrossRefGoogle Scholar
  237. 237.
    Nakamura Y, Xing Y, Sasano H, Rainey WE. The mediator complex subunit 1 enhances transcription of genes needed for adrenal androgen production. Endocrinology. 2009;150:4145–53.PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Viger RS, Guittot SM, Anttonen M, Wilson DB, Heikinheimo M. Role of the GATA family of transcription factors in endocrine development, function, and disease. Mol Endocrinol. 2008;22:781–98.PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Flück CE, Miller WL. GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by direct interaction with Sp1. Mol Endocrinol. 2004;18:1144–57.PubMedCrossRefGoogle Scholar
  240. 240.
    Huang YH, Lee CY, Tai PJ, Yen CC, Liao CY, Chen WJ, Liao CJ, Cheng WL, Chen RN, Wu SM, Wang CS, Lin KH. Indirect regulation of human dehydroepiandrosterone sulfotransferase family 1A member 2 by thyroid hormones. Endocrinology. 2006;147:2481–9.PubMedCrossRefGoogle Scholar
  241. 241.
    Martin LJ, Taniguchi H, Robert NM, Simard J, Tremblay JJ, Viger RS. GATA factors and the nuclear receptors SF-1/LRH-1 are key mutual partners in the regulation of the human HSD3B2 promoter. Mol Endocrinol. 2005;19:2358–70.PubMedCrossRefGoogle Scholar
  242. 242.
    Allen HL, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R, Ferrer J, Hattersley AT, Ellard S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet. 2012;44:20–2.CrossRefGoogle Scholar
  243. 243.
    Bonnefond A, Sand O, Guerin B, Durand E, De Graeve F, Huyvaert M, Rachdi L, Kerr-Conte J, Pattou F, Vaxillaire M, Polak M, Scharfmann R, Czernichow P, Froguel P. GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes. Diabetologia. 2012;55(10):2845–7.PubMedCrossRefGoogle Scholar
  244. 244.
    Maitra M, Koenig SN, Srivastava D, Garg V. Identification of GATA6 sequence variants in patients with congenital heart defects. Pediatr Res. 2010;68:281–5.PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Pihlajoki M, Gretzinger E, Cochran R, Kyrönlahti A, Schrade A, Hiller T, Sullivan L, Shoykhet M, Schoeller EL, Brooks MD, Heikinheimo M, Wilson DB. Conditional mutagenesis of Gata6 in SF1-positive cells causes gonadal-like differentiation in the adrenal cortex of mice. Endocrinology. 2013;154:1754–67.PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Heikinheimo M, Pihlajoki M, Schrade A, Kyronlahti A, Wilson DB. Testicular steroidogenic cells to the rescue. Endocrinology. 2015;156:1616–9.PubMedCrossRefGoogle Scholar
  247. 247.
    Padua MB, Jiang T, Morse DA, Fox SC, Hatch HM, Tevosian SG. Combined loss of the GATA4 and GATA6 transcription factors in male mice disrupts testicular development and confers adrenal-like function in the testes. Endocrinology. 2015;156(5):1873–86.PubMedPubMedCentralCrossRefGoogle Scholar
  248. 248.
    Tevosian SG, Jimenez E, Hatch HM, Jiang T, Morse DA, Fox SC, Padua MB. Adrenal development in mice requires GATA4 and GATA6 transcription factors. Endocrinology. 2015;156:2503–17.PubMedPubMedCentralCrossRefGoogle Scholar
  249. 249.
    Kyritsi, E. M., A. Sertedaki, G. Chrousos, and E. Charmandari, 2000. Familial or sporadic adrenal hypoplasia syndrome.Google Scholar
  250. 250.
    Malikova J, Flück CE. Novel insight into etiology, diagnosis and management of primary adrenal insufficiency. Horm Res Paediatr. 2014;82:145–57.PubMedCrossRefGoogle Scholar
  251. 251.
    Weber A, Clark AJ. Mutations of the ACTH receptor gene are only one cause of familial glucocorticoid deficiency. Hum Mol Genet. 1994;3:585–8.PubMedCrossRefGoogle Scholar
  252. 252.
    Metherell LA, Chapple JP, Cooray S, David A, Becker C, Ruschendorf F, Naville D, Begeot M, Khoo B, Nurnberg P, Huebner A, Cheetham ME, Clark AJ. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005;37:166–70.PubMedCrossRefGoogle Scholar
  253. 253.
    Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nurnberg P, Mann NP, Banerjee R, Saka HN, Chapple JP, King PJ, Clark AJ, Metherell LA. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency. Nat Genet. 2012;44:740–2.PubMedPubMedCentralCrossRefGoogle Scholar
  254. 254.
    Prasad R, Chan LF, Hughes CR, Kaski JP, Kowalczyk JC, Savage MO, Peters CJ, Nathwani N, Clark AJ, Storr HL, Metherell LA. Thioredoxin Reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J Clin Endocrinol Metab. 2014;99:E1556–63.PubMedPubMedCentralCrossRefGoogle Scholar
  255. 255.
    Prasad R, Metherell LA, Clark AJ, Storr HL. Deficiency of ALADIN impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis. Endocrinology. 2013;154:3209–18.PubMedPubMedCentralCrossRefGoogle Scholar
  256. 256.
    Arboleda VA, Lee H, Parnaik R, Fleming A, Banerjee A, Ferraz-de-Souza B, Delot EC, Rodriguez-Fernandez IA, Braslavsky D, Bergada I, Dell'angelica EC, Nelson SF, Martinez-Agosto JA, Achermann JC, Vilain E. Mutations in the PCNA-binding domain of CDKN1C cause IMAGe syndrome. Nat Genet. 2012;44(7):788–92.PubMedPubMedCentralCrossRefGoogle Scholar
  257. 257.
    Hughes CR, Guasti L, Meimaridou E, Chuang CH, Schimenti JC, King PJ, Costigan C, Clark AJ, Metherell LA. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest. 2012;122:814–20.PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Narumi S, Amano N, Ishii T, Katsumata N, Muroya K, Adachi M, Toyoshima K, Tanaka Y, Fukuzawa R, Miyako K, Kinjo S, Ohga S, Ihara K, Inoue H, Kinjo T, Hara T, Kohno M, Yamada S, Urano H, Kitagawa Y, Tsugawa K, Higa A, Miyawaki M, Okutani T, Kizaki Z, Hamada H, Kihara M, Shiga K, Yamaguchi T, Kenmochi M, Kitajima H, Fukami M, Shimizu A, Kudoh J, Shibata S, Okano H, Miyake N, Matsumoto N, Hasegawa T. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48(7):792–7.PubMedCrossRefGoogle Scholar
  259. 259.
    Roucher-Boulez F, Mallet-Motak D, Samara-Boustani D, Jilani H, Asmahane L, Souchon PF, Simon D, Nivot S, Heinrichs C, Ronze M, Bertagna X, Groisne L, Leheup B, Catherine NS, Blondin G, Lefevre C, Lemarchand L, Morel Y. NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects. Eur J Endocrinol. 2016;175(1):73–84.PubMedCrossRefGoogle Scholar
  260. 260.
    Toye AA, Lippiat JD, Proks P, Shimomura K, Bentley L, Hugill A, Mijat V, Goldsworthy M, Moir L, Haynes A, Quarterman J, Freeman HC, Ashcroft FM, Cox RD. A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia. 2005;48:675–86.PubMedCrossRefGoogle Scholar
  261. 261.
    Figueira TR. A word of caution concerning the use of Nnt-mutated C57BL/6 mice substrains as experimental models to study metabolism and mitochondrial pathophysiology. Exp Physiol. 2013;98:1643.PubMedCrossRefGoogle Scholar
  262. 262.
    Conrad M, Jakupoglu C, Moreno SG, Lippl S, Banjac A, Schneider M, Beck H, Hatzopoulos AK, Just U, Sinowatz F, Schmahl W, Chien KR, Wurst W, Bornkamm GW, Brielmeier M. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol. 2004;24:9414–23.PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Kiermayer C, Northrup E, Schrewe A, Walch A, de Angelis MH, Schoensiegel F, Zischka H, Prehn C, Adamski J, Bekeredjian R, Ivandic B, Kupatt C, Brielmeier M. Heart-specific knockout of the Mitochondrial Thioredoxin Reductase (Txnrd2) induces metabolic and contractile dysfunction in the aging myocardium. J Am Heart Assoc. 2015;4Google Scholar
  264. 264.
    Sibbing D, Pfeufer A, Perisic T, Mannes AM, Fritz-Wolf K, Unwin S, Sinner MF, Gieger C, Gloeckner CJ, Wichmann HE, Kremmer E, Schafer Z, Walch A, Hinterseer M, Nabauer M, Kaab S, Kastrati A, Schomig A, Meitinger T, Bornkamm GW, Conrad M, von Beckerath N. Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. Eur Heart J. 2011;32:1121–33.PubMedCrossRefGoogle Scholar
  265. 265.
    Handschug K, Sperling S, Yoon SJ, Hennig S, Clark AJ, Huebner A. Triple a syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Hum Mol Genet. 2001;10:283–90.PubMedCrossRefGoogle Scholar
  266. 266.
    Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, Edery P, Catala M, Odent S, Isidor B, Lyonnet S, Sigaudy S, Leheup B, Audebert-Bellanger S, Burglen L, Giuliano F, Alessandri JL, Cormier-Daire V, Laffargue F, Blesson S, Coupier I, Lespinasse J, Blanchet P, Boute O, Baumann C, Polak M, Doray B, Verloes A, Viot G, Le Bouc Y, Rossignol S. Mutations of the imprinted CDKN1C Gene as a cause of the overgrowth Beckwith-Wiedemann syndrome: clinical Spectrum and functional characterization. Hum Mutat. 2015;36:894–902.PubMedCrossRefGoogle Scholar
  267. 267.
    Casey JP, Nobbs M, McGettigan P, Lynch S, Ennis S. Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. J Med Genet. 2012;49:242–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Marjut Pihlajoki
    • 1
  • Markku Heikinheimo
    • 2
  • David B. Wilson
    • 3
  1. 1.Children’s Hospital, University of HelsinkiHelsinkiFinland
  2. 2.Children’s Hospital, University of HelsinkiHelsinkiFinland
  3. 3.Departments of Pediatrics and Developmental BiologyWashington University School of MedicineSt. LouisUSA

Personalised recommendations