**14. References**


[8] Schuster D, Laggner C, Steindl TM, Palusczak A, Hartmann RW, Langer T. Pharmacophore modeling and in silico screening fornewP450 19 (aromatase) inhibitors, Journal of Chemical Information & Modeling 2006; 46: 1301–1311.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 147

[23] Stocco DM.The Role of StAR in Leydig Cell Steroidogenesis. In: Payne AH. & Hardy MP. (eds) The Leydig Cell in Health and Disease. Totowa, NJ: Human Press Inc; 2007,

[24] Black SM, Harikrishna JA, Szklarz GD, Miller WL. The mitochondrial environment is required for activity of the cholesterol side-chain cleavage enzyme, cytochrome P450scc.

[25] Miller WL. Why nobody has P450scc(20,22 desmolase deficiency). Journal of Clinical

[26] Kim CJ, Lin L, Huang N, Quigley CA, AvRuskin TW, Achermann JC, Miller WL. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. Journal of Clincal Endocrinology and Metabolism

[27] Pang S, Yang X, Wang M, Tissot R, Nino M, Manaligod J, Bullock LP, Mason JI. Inherited congenital adrenal hyperplasia in the rabbit: absent cholesterol side-chain

[30] Martin RM, Lin CJ, Costa EM, de Oliveira ML, Carrilho A, Villar H, Longui CA, Mendonca BB. P450c17 deficiency in Brazilian patients: biochemical diagnosis through progesterone levels confirmed by CYP17 genotyping. Journal of Clinical Endocrinology

[31] Simard J, Ricketts ML, Gingras S, Soucy P, Feltus FA, Melner MH. Molecular biology of the 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase gene family.

[32] mas JL, Duax WL, Addlagatta A, Brandt S, Fuller RR, Norris W. Structure/function relationships responsible for coenzyme specificity and the isomerase activity of human type-1 3β-hydroxysteroid dehydrogenase/isomerase. Journal of Biological Chemistry

[33] Cherradi N, Defaye G, Chambaz EM. Dual subcellular localization of the 3βhydroxysteroid dehydrogenase isomerase: characterization of the mitochondrial enzyme in the bovine adrenal cortex. Journal Steroid Biochemistry & Molecular Biology

[34] Cherradi N, Chambaz EM, Defaye G. Organization of 3β-hydroxysteroid dehydrogenase/isomerase and cytochrome P450scc into a catalytically active molecular complex in bovine adrenocortical mitochondria. Journal Steroid Biochemistry &

[35] Pelletier G, Li S, Luu-The V, Tremblay Y, Belanger A, Labrie F. Immunoelectron microscopic localization of three key steroidogenic enzymes (cytochrome P450(scc), 3β-

cleavage cytochrome P450 gene expression. Endocrinology 1992;131, 181–186. [28] Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinology, Metabolism Clinics of North America 2001; 30, 101–119. [29] Van Den Akker EL, Koper JW, Boehmer AL, Themmen AP, Verhoef-Post M, Timmerman MA, Otten BJ, Drop SL, De Jong FH. Differential inhibition of 17 αhydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. Journal of Clinical Endocrinology &

Proceedings of the National Acadamy of Science USA 1994; 91: 7247–7251.

Endocrinology and Metabolism 1998;83: 1399–1400.

p149-155

2008; 93: 696-702.

Metabolism 2002; 87: 5714–5721.

& Metabolism 2003; 88: 5739–5746.

Endocrine Review 2005; 26: 525-582.

Molecular Biology 1995; 55: 507–514.

2003; 278: 483–490.

1993; 46, 773–779.


[23] Stocco DM.The Role of StAR in Leydig Cell Steroidogenesis. In: Payne AH. & Hardy MP. (eds) The Leydig Cell in Health and Disease. Totowa, NJ: Human Press Inc; 2007, p149-155

146 Dehydrogenases

212, 27-40.

87: 181-189.

275: 127–138.

2003 (1st edition) p1009-1110.

[8] Schuster D, Laggner C, Steindl TM, Palusczak A, Hartmann RW, Langer T. Pharmacophore modeling and in silico screening fornewP450 19 (aromatase) inhibitors,

[9] Aggarwal S, Thareja S, Verma A, Bhardwaj TR, Kumar K, An overview on 5alpha-

[10] Saloniemi T, Jokela H, Strauss L, Pakarinen P and Poutanen M. The diversity of sex steroid action: novel functions of hydroxysteroid (17*b*) dehydrogenases as revealed by genetically modified mouse models (Thematic Review). Journal of Endocrinology 2012:

[11] Hafez ESE. Hormones, Growth Factors, and Reproduction. In: Hafez ESE.(ed.)

[12] Barrett E. Section VIII The Endocrine System. In: Boron WF, Boulpaep EL (eds) Medical Physiology. A Cellular And Molecular Approach. Philadelphia, PA: Elsevier/Saunders;

[13] Pezzi V, Mathis JM, Rainey WE, Carr BG. Profiling transcript levels for steroidogenic enzymes in fetal tissues. Journal of Steroid Biochemistry and Molecular Biology 2003;

[14] Scott HM, Mason JI, Sharpe RM. Steroidogenesis in the fetal Testis and its Susceptibility to Disruption by Exogenous Compounds. Endocrine Review 2009; 30: 883-925. [15] Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from

[16] Payne AH. Steroidogenic Enzymes in Leydig Cells. In: Payne AH. & Hardy MP. (eds) The Leydig Cell in Health and Disease. Totowa, NJ: Human Press Inc; 2007, p157-171. [17] Arakane F, Kallen CB, Watari H, Foster JA, Sepuri NB, Pain D, Stayrook SE, Lewis M, Gerton GL, Strauss 3rd JF. The mechanism of action of steroidogenic acute regulatory protein (StAR). StAR acts on the outside of mitochondria to stimulate steroidogenesis. J

[18] Dube´ C, Bergeron F, Vaillant MJ, Robert NM, Brousseau C, Tremblay JJ. The nuclear receptors SF1 and LRH1 are expressed in endometrial cancer cells and regulate steroidogenic gene transcription by cooperating with AP-1 factors. Cancer Letters 2009;

[19] Parker KL, Schimmer BP. Transcriptional regulation of the genes encoding the cytochrome P-450 steroid hydroxylases. Vitamins and Hormones 1995; 51: p339–370. [20] O'Shaughnessy PJ, Johnston H, Baker PJ. Development of Leydig Cell Steroidogenesis. In: Payne AH. & Hardy MP. (eds) The Leydig Cell in Health and Disease. Totowa, NJ:

[21] Achermann JC, Ozisik G, Ito M, Orun UA, Harmanci K, Gurakan B, Jameson JL. Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner. Journal of Clinical

[22] Jeyasuria P, Ikeda Y, Jamin SP, Zhao L, De Rooij DG, Themmen AP, Behringer RR, Parker KL. Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in

cholesterol to active steroid hormones. Endocrine Review 2004; 25: 947-970.

Reproduction in Farm Animals. Philadelphia: Lea & Febiger; 1993. p59-93.

Journal of Chemical Information & Modeling 2006; 46: 1301–1311.

reductase inhibitors. Steroids 2010; 75: 109–153.

Biological Chemistry 1998; 273: 16339–16345.

Endocrinology and Metabolism 2002; 87: 1829–1833.

gonadal function. Molecular Endocrinology 2004;1: 1610–1619.

Human Press Inc; 2007, p173-179.


hydroxysteroid dehydrogenase and cytochrome P450(c17)) in rat adrenal cortex and gonads. Journal of Endocrinology 200; 171: 373–383.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 149

[47] Mason JI, Howe BE, Howie AF, Morley SD, Nicol MR, Payne AH. Promiscuous 3βhydroxysteroid dehydrogenases: testosterone 17β-hydroxysteroid dehydrogenase activities of mouse type I and VI 3β-hydroxysteroid dehydrogenases. Endocrine

[48] Payne AH, Clarke TR, Bain PA. The murine 3β-hydroxysteroid dehydrogenase multigene family: structure, function and tissue-specific expression. Journal Steroid

[49] Payne AH, Abbaszade IG, Clarke TR, Bain PA, Park CH. The multiple murine 3β hydroxysteroid dehydrogenase isoforms: structure, function, and tissue- and

[50] Abbaszade IG, Arensburg J, Park CH, Kasa-Vubu JZ, Orly J, Payne AH 1997 Isolation of a new mouse 3β-hydroxysteroid dehydrogenase isoform, 3β-HSD VI, expressed during

[51] Belanger B, Belanger A, Labrie F, Dupont A, Cusan L, Monfette G. 1989 Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after castration: unique importance of extratesticular androgens in men. Journal of Steroid

[52] Dupont E, Luu-The V, Labrie F, Pelletier G. Ontogeny of 3β-hydroxysteroid dehydrogenase/∆5-∆4 isomerase (3β-HSD) in human adrenal gland performed by

[54] Lo MJ, Kau MM, Chen YH, Tsai SC, Chiao YC, Chen JJ, Liaw C, Lu CC, Lee BP, Chen SC, Fang VS, Ho LT, Wang PS. Acute effects of thyroid hormones on the production of adrenal cAMP and corticosterone in male rats. American Journal of Physiology 1998;

[55] Dupont E, Labrie F, Luu-The V, Pelletier G. Immunocytochemical localization of 3βhydroxysteroid dehydrogenase/∆5-∆4 isomerase in human ovary. Journal of Clinical

[56] Kaplan S, Grumach M. Pituitary and placental gonadotropin and sex steroids in the human and sub-human primate fetus. Journal of Clinical Endocrinology & Metabolism

[57] Grumbach M, Conte F. Disorders of sex differentitiation. In: Wilson JD & Foster EW (eds) Williams textbook of endocrinology. Philadelphia: W. B. Saunders; 1999: 1303–

[58] Nelson VL, Legro RS, Strauss 3rd JF, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries.

[59] Doody KJ, Lorence MC, Mason JI, Simpson ER. Expression of messenger ribonucleic acid species encoding steroidogenic enzymes in human follicles and corpora lutea throughout the menstrual cycle. Journal of Clinical Endocrinology & Metabolism 1990;

immunocytochemistry. Molecular & Cellular Endocrinology 1990; 74: R7–R10. [53] Simonian MH. ACTH and thyroid hormone regulation of 3β-hydroxysteroid dehydrogenase activity in human fetal adrenocortical cells. Journal Steroid Biochem

Research 2004; 30: 709–714.

Biochemestry 1989; 32: 695–698.

1986; 25: 1001–1006.

274: E238–E245.

1978; 7: 487–511.

70: 1041–1045.

1425

Biochemistry & Molecular Biology 1995; 53: 111–118.

early pregnancy. Endocrinology 1998; 138: 1392–1399.

Endocrinology & Metabolism 1992; 74: 994–998.

Molecular Endocrinology 1999; 13: 946–957.

developmentally specific expression. Steroids 1997; 62: 169–175.


[47] Mason JI, Howe BE, Howie AF, Morley SD, Nicol MR, Payne AH. Promiscuous 3βhydroxysteroid dehydrogenases: testosterone 17β-hydroxysteroid dehydrogenase activities of mouse type I and VI 3β-hydroxysteroid dehydrogenases. Endocrine Research 2004; 30: 709–714.

148 Dehydrogenases

1992; 267: 3551

266: 583–593.

1992; 131: 3034–3044.

Endocrinolology 1994; 103: 29–38.

isomerase. Endocrinology 1992; 130: 553–555.

hydroxysteroid dehydrogenase and cytochrome P450(c17)) in rat adrenal cortex and

[36] Chapman JC, Waterhouse TB, Michael SD. Changes in mitochondrial and microsomal 3\_-hydroxysteroid dehydrogenase activity in mouse ovary over the course of the

[37] Luu-The V, Lachance Y, Labrie C, Leblanc G, Thomas JL, Strickler RC, Labrie F. Full length cDNA structure and deduced amino acid sequence of human 3β-hydroxy-5-ene

[38] Rheaume E, Lachance Y, Zhao HF, Breton N, Dumont M, de Launoit Y, Trudel C, Luu-The V, Simard J, Labrie F. Structure and expression of a new complementary DNA encoding the almost exclusive 3β-hydroxysteroid dehydrogenase/ ∆5-∆4-isomerase in

[39] Dumont M, Luu-The V, Dupont E, Pelletier G, Labrie F. Characterization, expression, and immunohistochemical localization of 3β-hydroxysteroid dehydrogenase/∆5-∆4

[41] Morissette J, Rheaume E, Leblanc JF, Luu-The V, Labrie F, Simard J 1995 Genetic linkage mapping of HSD3B1 and HSD3B2 encoding human types I and II 3β-hydroxysteroid dehydrogenase/∆5-∆4- isomerase close to D1S514 and the centromeric D1Z5 locus.

[42] Zhao HF, Labrie C, Simard J, de Launoit Y, Trudel C, Martel C, Rheaume E, Dupont E, Luu-The V, Pelletier G. Characterization of rat 3β-hydroxysteroid dehydrogenase/∆5-∆4 isomerase cDNAs and differential tissue-specific expression of the corresponding mRNAs in steroidogenic and peripheral tissues. Journal of Biological Chemistry 1991;

[43] Simard J, Couet J, Durocher F, Labrie Y, Sanchez R, Breton N, Turgeon C, Labrie F. Structure and tissue-specific expression of a novel member of the rat 3β-hydroxysteroid dehydrogenase/ ∆5-∆4 isomerase (3β-HSD) family. The exclusive 3β-HSD gene

[45] Sanchez R, de Launoit Y, Durocher F, Belanger A, Labrie F, Simard J. Formation and degradation of dihydrotestosterone by recombinant members of the rat 3βhydroxysteroid dehydrogenase/ ∆5-∆4 isomerase family. Molecular & Cellular

[46] de Launoit Y, Simard J, Durocher F, Labrie F. Androgenic 17β-hydroxysteroid dehydrogenase activity of expressed rat type I 3β-hydroxysteroid dehydrogenase/∆5-∆4

expression in the skin. Journal of Biological Chemistry1993; 268: 19659–19668. [44] Couet J, Simard J, Martel C, Trudel C, Labrie Y, Labrie F. Regulation of 3-ketosteroid reductase messenger ribonucleic acid levels and 3β-hydroxysteroid dehydrogenase/∆5- ∆4 isomerase activity in rat liver by sex steroids and pituitary hormones. Endocrinology

isomerase in human skin. Journal of Investigave Dermatology 1992; 99: 415–421. [40] Lachance Y, Luu-The V, Labrie C, Simard J, Dumont M, de Launoit Y, Guerin S, Leblanc G, Labrie F. Characterization of human 3β-hydroxysteroid dehydrogenase/∆5-∆4 isomerase gene and its expression in mammalian cells. Journal of Biological Chemistry

gonads. Journal of Endocrinology 200; 171: 373–383.

estrous cycle. Biology of Reproduction 1992; 4: 992–997.

Cytogenetics & Cell Genetics 1995; 69: 59–62.

steroid dehydrogenase. Molecular Endocrinology 1989; 3: 1310–1312.

human adrenals and gonads. Molecular Endocrinology 1991; 5: 1147–1157.


[60] Teerds KJ, Dorrington JH. Immunohistochemical localization of 3β-hydroxysteroid dehydrogenase in the rat ovary during follicular development and atresia. Biology of Reprod 1993; 49: 989–996.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 151

[74] Bernstein L, Ross RK 1993 Endogenous hormones and breast cancer risk. Epidemiology

[75] Gunasegaram R, Peh KL, Loganath A, Ratnam SS. Expression of 3β-hydroxysteroid dehydrogenase-5,4-ene isomerase activity by infiltrating ductal human breast

[76] Reed MJ, Purohit A. Breast cancer and the role of cytokines in regulating estrogen

[77] Turgeon C, Gingras S, Carriere MC, Blais Y, Labrie F, Simard J. Regulation of sex steroid formation by interleukin-4 and interleukin-6 in breast cancer cells. Journal of

[78] Riley SC, Dupont E, Walton JC, Luu-The V, Labrie F, Pelletier G,Challis JR. Immunohistochemical localization of 3β-hydroxy- 5-ene-steroid dehydrogenase/∆5-∆4 isomerase in human placenta and fetal membranes throughout gestation. Journal of

[79] Morrish DW, Linetsky E, Bhardwaj D, Li H, Dakour J, Marsh RG, Paterson MC, Godbout R. Identification by subtractive hybridization of a spectrum of novel and unexpected genes associated with in vitro differentiation of human cytotrophoblast

[80] Amet Y, Simon B, Quemener E, Mangin P, Floch HH, Abalain JH. Partial purification of 3α- and 3β-hydroxysteroid dehydrogenases from human hyperplastic prostate. Comparison between the two enzymes. Journal of Steroid Biochemistry & Molecular

[81] Labrie F, Belanger A, Cusan L, Labrie C, Simard J. History of LHRH agonist and combination therapy in prostate cancer. Endocrine Related Cancer 1996; 3, 243–278 [82] Pirog EC, Collins DC 1999 Metabolism of dihydrotestosterone in human liver: importance of 3α- and 3β-hydroxysteroid dehydrogenase. Journal of Clinical

[83] Keeney DS, Murry BA, Bartke A, Wagner TE, Mason JI 1993 Growth hormone transgenes regulate the expression of sex-specificisoforms of 3β-hydroxysteroid dehydrogenase/∆5-∆4 isomerase in mouse liver and gonads. Endocrinology 1993; 133:

[84] Anderson D. Steroidogenic enzymes in skin. Journal of Dermatology 2001; 11, 293-295. [85] Asada H, Linton J, Katz SI 1997 Cytokine gene expression during the elicitation phase of contact sensitivity: regulation by endogenous IL-4. Journal of Investigarive

[86] Mensah-Nyagan AG, Do-Rego JL, Beaujean D, Luu-The V, Pelletier G, Vaudry H 1999 Neurosteroids: expression of steroidogenic enzymes and regulation of steroid biosynthesis in the central nervous system. Pharmacology Review 1999; 51: 63–81. [87] Zwain IH, Yen SS 1999 Neurosteroidogenesis in astrocytes, oligodendrocytes, and

[88] Baker PJ, Johnston H, Abel M, HM C, O'Shaughnessy PJ. Differentiation of adult-type Leydig cells occurs in gonadotropin-deficient mice. Reproductive Biology &

neurons of cerebral cortex of rat brain. Endocrinology 1999; 140: 3843–3852.

carcinoma in vitro. Breast Cancer Research & Treatment 1998; 50: 117–123.

synthesis: an emerging hypothesis. Endocine Review 1997; 18: 701–715.

Steroid Biochemistry & Molecular Biology 1998; 65: 151–162,

Clinical Endocrinology & Metabolism 1992; 75: 956–961.

Endocrinology & Metabolism 1999; 84: 3217–3221.

Review 1993; 15 :48–65.

cells. Placenta 1996; 17: 431–441

Dermatology 1997; 108: 406–411.

Endocrinology 2003; 1: 1–9.

Biology 1992; 41: 689–692.

1131–1138.


[74] Bernstein L, Ross RK 1993 Endogenous hormones and breast cancer risk. Epidemiology Review 1993; 15 :48–65.

150 Dehydrogenases

Reprod 1993; 49: 989–996.

Reproductive Endocrinology 1997; 15: 345–351.

Molecular Endocrinology 1999; 13: 1084–1093.

Biology 2005; 167: 935-944.

2012, Stockholm, Sweeden.

Sciences, Sofia, 2007.

primate corpus luteum. Endocrinology 1993; 133: 699–704,

of the Society for Gynecologic Investigations 1995; 2:535–541.

1993; 132: 888–894.

2396–2402.

[60] Teerds KJ, Dorrington JH. Immunohistochemical localization of 3β-hydroxysteroid dehydrogenase in the rat ovary during follicular development and atresia. Biology of

[61] Voss AK, Fortune JE. Levels of messenger ribonucleic acid for cholesterol side-chain cleavage cytochrome P-450 and 3β-hydroxysteroid dehydrogenase in bovine preovulatory follicles decrease after the luteinizing hormone surge. Endocrinology

[62] Labrie F, Belanger A, Cusan L, Gomez JL, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. Journal of Clinical Endocrinology & Metabolism 1997; 82:

[63] Sasano H, Suzuki T. Localization of steroidogenesis and steroid receptors in human corpus luteum. Classification of human corpus luteum (CL) into estrogen- producing degenerating CL, and nonsteroid-producing degenerating CL. Seminars of

[64] Duncan WC, Cowen GM, Illingworth PJ. Steroidogenic enzyme expression in human corpora lutea in the presence and absence of exogenous human chorionic

[65] Benyo DF, Little-Ihrig L, Zeleznik AJ. Noncoordinated expression of luteal cell messenger ribonucleic acids during human chorionic gonadotropin stimulation of the

[66] McGee E, Sawetawan C, Bird I, Rainey WE, Carr BR. The effects of insulin on 3βhydroxysteroid dehydrogenase expression in human luteinized granulosa cells. Journal

[67] Feltus FA, Groner B, Melner MH. Stat5-mediated regulation of the human type II 3βhydroxysteroid dehydrogenase/∆5-∆4 isomerase gene: activation by prolactin.

[68] Stocco CO, Deis RP. Participation of intraluteal progesterone and prostaglandin F2α in

[69] Mendis-Handagama SMLC, Ariyaratne HBS. Differentiation of adult Leydig cell proliferation in the postnatal testis. Biology of Reproduction 2001; 65: 660-671. [70] Davidoff MS, Middendorff R, Enikolopov G, Riethmacher D, Holstein AF, Muller D. Progenitor cells of the testosterone-producing Leydig cells revealed. Journal of Cell

[71] Kilcoyne K, Sharpe RM, McKinnell C, van den Driesche S, Smith LB, Atanossova N. Putative adult Leydig progenitor cells in the rat are reduced in number following DBPinduced suppression of fetal intratesticular testosterone. Proceedings of 17th European Testis Workshop on Molecilar and Cellular Endocrinology of the Testis. April 20-24

[72] Atanassova N. Morpho-functional aspect of androgen-estrogen regulation of mammalian testis and male reproductive tract. DSci Thesis, Bulgarian Academy of

[73] Habert R, Lejeune H, Saez JM. Origin, differentiation and regulation of fetal and adult

Leydig cells. Molecular and Cellular Endocrinology 2001; 179: 47-74.

LH-induced luteolysis in pregnant rat. J Endocrinol 1998; 156: 253–259.

gonadotrophin (HCG). Molecular & Human Reproduction 1999; 5: 291–298.


[89] Martin LJ, Taniguchi H, Robert NM, Simard J, Tremblay JJ, Viger RS. GATA Factors and the Nuclear Receptors, Steroidogenic Factor 1/Liver Receptor Homolog 1, Are Key Mutual Partners in the Regulation of the Human 3β-Hydroxysteroid Dehydrogenase Type 2 Promoter. Molecular Endocrinology 2005; 19: 2358–2370.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 153

[104] Seckl JR, Walker BR. Minireview: 11ß-hydroxysteroid dehydrogenase type 1- a tissuespecific amplifier of glucocorticoid action. Endocrinology 2001; 142: 1371-1376. [105] Albiston AL, Obeyesekere VR, Smith RE and Krozowski ZS. Cloning and tissue distribution of the human 11β -hydroxysteroid dehydrogenase type 2 enzyme

[106] MercerWR and Krozowski ZS. Localization of an 11\_-hydroxysteroid dehydrogenase activity to the distal nephron. Evidence for the existence of two species of

[107] Brown RW, Chapman KE, Edwards CRW and Seckl JR. Human placental 11βhydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD-

[108] Seckl JR, Morton NM, Chapman KE, Walker BR. Glucocorticoids and 11betahydroxysteroid dehydrogenase in adipose tissue. Recent Progess in Hormone Research

[109] Ge RS, Hardy DO, Catterall JE, Hardy MP. Developmental changes in glucocorticoid receptor and 11ß–hydroxysteroid dehydrogenase oxidative and reductive activities in

[110] Ge RS, Hardy MP. Initial predominance of the oxidative activity of type 11ßhydroxysteroid dehydrogenase in primary rat Leydig cells and transfected cell lines.

[111] Monder C, Miroff Y, Marandici A, Hardy MP. 11ß–dehydrogenase alleviates glucocorticoid-mediated inhibition of steroidogenesis in rat Leydig cells. Endocrinology

[112] Phillips DM, Lakshmi V, Moder C. Corticosteroid 11ß–hydroxysteroid dehydrogenase

[113] Hales DB, Payne AH. Glucocorticoid-mediated repression of P450scc mRNA and de

[116] Gao HB, Tong MH, Hu YQ, You HY, Guo QS, Ge RS, Hardy MP. Mechanisms of glucocorticoidinduced Leydig cell apoptosis. Molecular & Cellular Endocrinology 2003;

[117] Guo-Xin Hu, Qing-Quan Lian, Han Lin, Syed A. Latif, David J. Morris, Matthew P. Hardy, and Ren-Shan Ge. Rapid mechanisms of glucocorticoid signaling in the Leydig

[118] Gao HB, Ge RS, Lakshmi A, Hardy MP. Hormonal regulation of oxidative and reductive activities of 11ß–hydroxysteroid dehydrogenase in rat Leydig cells.

novo synthesis in cultured Leydig cells. Endocrinology 1989; 124: 2099–2104. [114] Payne AH, Sha LL. Multiple mechanisms for regulation of 3b-hydroxysteroid dehydrogenase/D5-D4-isomerase, 17a-hydroxylase/C17-20 lyase cytochrome P450, and cholesterol side-chain cleavage cytochrome P450 messenger ribonucleic acid levels in

primary cultures of mouse Leydig cells. Endocrinology 1991; 129: 1429–1435. [115] Gao HB, Tong MH, Hu YQ, Guo QS, Ge R, Hardy MP. Glucocorticoid induces

apoptosis in rat Leydig cells. Endocrinology 2002; 143: 130–138.

Molecular and Cellular Endocrinology 1994; 105: R11–R17.

dependent iosform. Endocrinology 1993; 132: 2614–2621.

rat Leydig cells. Endocrinology. 1997;138: 5089-95.

Journal of Andrology 2000; 21: 303-310.

in rat testis. Endocrinology 1989;125: 209-216.

2004; 59: 359-93.

1994; 134: 1199-1204.

199: 153–163.

cell. Steroids 2008; 73: 1018–1024.

Endocrinology 1997; 138: 156-161.

dehydrogenase in the rat kidney.Endocrinology1992; 130: 540–543.


[104] Seckl JR, Walker BR. Minireview: 11ß-hydroxysteroid dehydrogenase type 1- a tissuespecific amplifier of glucocorticoid action. Endocrinology 2001; 142: 1371-1376.

152 Dehydrogenases

[89] Martin LJ, Taniguchi H, Robert NM, Simard J, Tremblay JJ, Viger RS. GATA Factors and the Nuclear Receptors, Steroidogenic Factor 1/Liver Receptor Homolog 1, Are Key Mutual Partners in the Regulation of the Human 3β-Hydroxysteroid Dehydrogenase

[91] und S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN. Stat5a and Stat5b proteins have essential and

[93] Tremblay JJ, Viger RS. Novel roles for GATA transcription factors in the regulation of steroidogenesis. Journal of Steroid Biochemestry & Molecular Biology 2003; 85: 291–298. [94] Cote S, Feltus AF, Gingras S, Freeman M, Melner MH, Simard J 2000 IL-4 stimulation of ovarian 3β-hydroxysteroid dehydrogenase/ ∆5-∆4-isomerase type II gene expression: mechanisms of activation. Proceedings of the 82nd Annual Meeting of The Endocrine

[95] Rainey WE, Naville D, Mason JI. Regulation of 3β-hydroxysteroid dehydrogenase in adrenocortical cells: effects of angiotensin- II and transforming growth factor β.

[96] Havelock JC, Smith AL, Seely JB, Dooley CA, Rodgers RJ, Rainey WE, Carr BR. The NGFI-B family of transcription factors regulates expression of 3β-hydroxysteroid dehydrogenase type 2 in the human ovary. Molecular & Human Reproduction 2005; 11:

[97] Martin LJ, Tremblay J. The human 3β-hydroxysteroid dehydrogenase/∆5-∆4 isomerase type 2 promoter is a novel target for the immediate early orphan nuclear receptor

[98] Feltus FA, Cote S, Simard J, Gingras S, Kovacs WJ, Nicholson WE, Clark BJ, Melner MH. Glucocorticoids enhance activation of the human type II 3β-hydroxysteroid dehydrogenase/∆5-∆4 isomerase gene. Journal of Steroid Biochemistry & Molecular

[99] Perry JE, Stalvey JR. Gonadal steroids modulate adrenal fasciculata 3β-hydroxysteroid dehydrogenase isomerase activity in mice. Biology of Reproduction 1992; 46: 73–82. [100] Stalvey JR, Clavey SM. Evidence that testosterone regulates Leydig cell 3βhydroxysteroid dehydrogenase-isomerase activity by a trans-acting factor distal to the

[101] Bush IE, Hunter SA and Meigs RA. Metabolism of 11-oxygenated steroids Biochemical

[102] Lakshmi V and Monder C. Purification and characterization of the corticosteroid 11βdehydrogenase component of the rat liver 11β- hydroxysteroid dehydrogenase complex

[103] Jamieson PM, Chapman KE, Walker BR, Seckl JR. 11β -hydroxysteroid dehydrogenase type 1 is a predominant 11-reductase in the intact perfused rat liver. Journal of

nonessential, or redundant, roles in cytokine responses. Cell 1998; 93: 841–850. [92] Lalli E, Bardoni B, Zazopoulos E, Wurtz JM, Strom TM, Moras D, Sassone-Corsi P. A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia

Type 2 Promoter. Molecular Endocrinology 2005; 19: 2358–2370. [90] Darnell Jr JE. STATs and gene regulation. Science1997; 277: 1630–1635.

congenita. Molecular Endocrinology 1997; 11: 1950–1960.

Society, 2000, Toronto, Ontario, p 313 (Abstract 1295).

Nur77 in steroidogenic cells. Endocrinology 2005;146: 861–869

androgen receptor. Journal of Andrology 1992; 13: 93–99.

Endocrine Research 1991; 17: 281–296

79–85

Biology 2002; 82: 55–63.

Journal 1968; 107: 239–258.

Endocrinology 1988; 123: 2390–2398.

Endocrinol 2000; 165: 685–692.


[119] Jamieson PM, Walker BR, Hapman KE, Andrew R, Rossiter S, Seckl JR. 11 betahydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the perfused rat liver. Journal of Endocrinology 2000; 165: 685-692.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 155

dimethanesulphonate treatment of adult rats. Folia Histochemica & Cytobiologica 2007;

[134] Bakalska M, Atanassova N, Angelova P, Koeva I, Nikolov B, Davidoff M. Degeneration and restoration of spermatogenesis in relation to the changes in Leydig cell population following ethane dimethanesulfonate treatment in adult rats. Endocrine

[135] Bakalska M, Koeva I, Atanassova N, Angelova P, Nikolov B, Davidoff M. Steroidogenic and structural differentiation of new Leydig cell population following exposure of adult rats to ethane dimethanesulphonate. Folia Biologica (Praha) 2002; 48:

[136] Ge RS, Dong Q, Niu EM, Sottas CM, Hardy DO, Catterall JF, Latif SA, Morris DJ, Hardy MP. 11 beta-hydroxysteroid dehydrogenase 2 in rat Leydig cells: its role in blunting glucocorticoid action at physiological levels of substrate. Endocrinology 2005;

[137] Hardy M and Schlegel P. Testosterone production in the aging male: Where does the

[138] Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. Journal of Clinical Endocrinology & Metabolism 2001; 86:

[139] Wang C, Hikim AS, Ferrini M, Bonavera JJ, Vemet D, Leung A, Lue YH, Gonzalez-Cadavid NF, Schwerdloff RS. Male reproductive ageing: using the brown Norway rat as

[140] Chen H, Huhtaniemi I, Zirkin BR. Depletion and repopulation of Leydig cells in the

[141] Zirkin BR and Chen H. Regulation of Leydig cell steroidogenic function during aging.

[142] Chen H, Luo L, Zirkin BR. Leydig cell structure and function during aging. In: Payne AH, Hardy MP, Russell LD, eds. The Leydig cell. Cache River Press, Vienna, IL; 1996:

[143] Schultz R, Isola J, Parvinen M, Honkaniemi J, Wikstrom AC, Gustafsson JA, Pelto-Huikko M. Localization of the glucocorticoid receptor in testis and accessory sexual

[144] Monder C, White PC. 11 hydroxysteroid dehydrogenase. Vitamines & Hormones

[145] Walker BR, Connacher AA, Lindsay RM, Webb DJ, Edwards CR. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. Journal of Clinical Endocrinology &

[146] Koeva Y, Bakalska M, Atanassova N, Georgieva K, Davidoff M. Age-related changes in the expression of 11beta-hydroxysteroid dehydrogenase type 2 in rat Leydig cells.

[147] Sankar BR, Maran RR, Sudha S, Govindarajulu P, Balasubramanian K. Chronic corticosterone treatment impairs Leydig cell 11beta-hydroxysteroid dehydrogenase

slowdown occur? Endocrinology 2004; 145: 4439-40.

Biology of Reproduction 2000;63: 977-81.

a model for man. Novartis Found Symposium. 2002; 242: 82-95.

testes in aging Brown Norway rats. Endocrinology 1996; 137: 3447-52.

organs of male rat. Molecular & Cellular Endocrinology 1993; 95:115-20.

45: 381-6.

205-209.

724-31.

p221-30.

1993; 47: 187-271.

Metabolism 1995; 80 :3155-59.

Folia Histochemica & Cytobiologica 2009; 47: 281-287.

146: 2657-2664.

Regulations 2001; 35: 211-217.


dimethanesulphonate treatment of adult rats. Folia Histochemica & Cytobiologica 2007; 45: 381-6.

[134] Bakalska M, Atanassova N, Angelova P, Koeva I, Nikolov B, Davidoff M. Degeneration and restoration of spermatogenesis in relation to the changes in Leydig cell population following ethane dimethanesulfonate treatment in adult rats. Endocrine Regulations 2001; 35: 211-217.

154 Dehydrogenases

[119] Jamieson PM, Walker BR, Hapman KE, Andrew R, Rossiter S, Seckl JR. 11 betahydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the

[120] Seckl JR, Walker BR. Minireview: 11ß-hydroxysteroid dehydrogenase type 1- a tissuespecific amplifier of glucocorticoid action. Endocrinology 2001; 142: 1371-1376. [121] Latif SA, Shen M, Ge RS, Sottas CM, Hardy MP, Morris DJ. Role of 11β-OH-C(19) and C(21) steroids in the coupling of 11β-HSD1 and 17β-HSD3 in regulation of testosterone

[122] Hu GX, Lin H, Sottas CM, Morris DJ, Hardy MP, Ge RS. Inhibition of 11betahydroxysteroid dehydrogenase enzymatic activities by glycyrrhetinic acid in vivo supports direct glucocorticoid-mediated suppression of steroidogenesis in Leydig cells.

[123] Parthasarathy C, Yuvaraj S, Ilangovan R, Janani P, Kanagaraj P, Balaganesh M, Natarajan B, Sittadjody S, Balasubramanian K. Differential response of Leydig cells in expressing 11beta-HSD type I and cytochrome P450 aromatase in male rats subjected to

[125] Monder C, Hardy MP, Blanchard RJ, Blanchard DC. Comparative aspects of 11ßhydroxysteroid dehydrogenase: development of a model for the mediation of Leydig

[126] Neumann A, Haider SG, Hilscher B. Temporal coincidence of the appearance of elongated spermatids and of histochemical reaction of 11ß–hydroxysteroid

[127] Schafers BA, Schlutius BG, Haider SG. Ontogenesis of oxidative reaction of 17βhydroxysteroid dehydrogenese and 11ß–hydroxysteroid dehydrogenase in rat Leydig

[128] Ge RS, Gao HB, Nacharaju VL, Gunsalus GL, Hardy MP. Identification of a kinetically distinct activity of 11ß–hydroxysteroid dehydrogenase in rat Leydig cells.

[129] Brereton PS, Van Driel RR, Suhaimi FB, Koyama K, Dilley R, Krozowski Z. Light and electron microscopy localization of the 11ß-hydroxysteroid dehydrogenase type I

[130] Hardy MP, Gao HB, Dong Q, Ge R, Wang Q, Chai WR, Feng X, Sottas C. Stress hormone and male reproductive function.Cell & Tissue Research 2005; 322:147-53. [131] Ge RS, Dong Q, Sottas CM, Chen H, Zirkin BR, Hardy MP. Gene expression in rat Leydig cells during development from the progenitor to adult stage: a cluster analysis.

[132] Hu GX, Lian QQ, Chen BB, Prasad PV, Kumar N, Zheng ZQ, Ge RS. 7alphahydroxytestosterone affects 1 beta-hydroxysteroid dehydrogenase 1 direction in rat

[133] Koeva Y, Bakalska M, Atanassova N, Georgieva K, Davidoff M. 11 hydroxysteroid dehydrogenase type 2 expression in the newly formed Leydig cells after ethane

corticosterone deficiency. Molecular & Cellular Endocrinology 2009; 311:18-23. [124] Haider SG, Passia D, Rommert FFG. Histochemical demonstration of 11ß– hydroxysteroid dehydrogenase as a marker for Leydig cell maturation in rat. Acta

perfused rat liver. Journal of Endocrinology 2000; 165: 685-692.

biosynthesis in rat Leydig cells. Steroids 2011; 76: 682-689.

cell function by corticosteroids. Steroids 1994; 59: 69-73.

enzyme in the rat. Endocrinology 2001; 142: 1644-1651.

Biology of Reproduction 2005; 72: 1405-1415.

Leydig cells. Endocrinology 2010; 151: 748-54.

dehydrogenase in rat Leydig cells. Andrologia 1993; 25: 263-269.

cells, a histochemical study. The Histochemical Journal 2001; 33: 585-595.

Journal of Andrology 2008; 29: 345-51.

Histochemica (Suppl) 1990; 38: 203-207.

Endocrinology 1997;138: 2435-2442.


activity and LH-stimulated testosterone production. Hormone & Metabolism Research 2000; 32: 142-146.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 157

[162] Yding Andersen C, Morineau G, Fukuda M, Westergaard LG, Ingerslev HJ, Fiet J & Byskov AG. Assessment of the follicular cortisol:cortisone ratio. Human Reproduction

[163] Yong PYK, Thong KJ, Andrew R, Walker BR & Hillier SG. Development-related increase in cortisol biosynthesis by human granulosa cells. Journal of Clinical

[164] Hillier SG & Tetsuka M. An anti-inflammatory role for glucocorticoids in the ovaries?

[165] Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R. Prevalence of the polycystic ovary syndrome in unselected black and white women of the Southeastern United States: a prospective study. Jornal of Clinical Endocrinology &

[166] Legro, R.S. & J.F. Strauss III. Molecular progress in infertility: polycystic ovary

[167] Milutinović DV, Macut D, Božić I, Nestorov J, Damjanović S, Matić G. Hypothalamicpituitary-adrenocortical axis hypersensitivity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome. Experimental Clinical

[168] Diamanti-Kandarakis E, Xyrafis X, Boutzios G, Christakou C. Pancreatic beta-cells dysfunction in polycystic ovary syndrome. Panminerva Medicine 2008; 50: 315-25. [169] Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nature Reviews of Endocrinology 2011;7 :219-31. [170] Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S, Conway GS, White D, Todd JA, Franks S, Williamson R. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 1997; 349: 986–990. [171] Nelson VL, Legro RS, Strauss JF 3rd, McAllister JM.. Augmented androgen production is a stable phenotype of propagated theca cells from polycystic ovaries. Molecular

[172] Nelson VL, Qin KN, Rosenfield RL, Wood JR, Penning TM, Legro RS, Strauss JF 3rd, McAllister JM.The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. Journal of Clinical

[173] Wickenheisser JK, Quinn PG, Nelson VL, Legro RS, Strauss JF 3rd, McAllister JM. Differential activity of the cytochrome P450 17 α-hydroxylase and steroidogenic acute regulatory protein gene promoters in normal and polycystic ovary syndrome theca

[174] J.F.Strauss III. Some New Thoughts on the Pathophysiology and Genetics of Polycystic Ovary Syndrome. Annals of New York Academy of Sciences 2003; 997: 42–48. [175] Svendsen PF, Madsbad S, Nilas L, Paulsen SK, Pedersen SB. Expression of 11betahydroxysteroid dehydrogenase 1 and 2 in subcutaneous adipose tissue of lean and obese women with and without polycystic ovary syndrome. International Journal of

[176] Tsilchorozidou T, Honour JW, Conway GS. Altered cortisol metabolism in polycystic ovary syndrome: insulin enhances 5alpha-reduction but not the elevated adrenal

cells. Journal of Clinical Endocrinology and Metabolism 2000; 85: 2304–2311.

Endocrinology and Metabolism 2000; 85: 4728–4733.

Journal of Reproductive Immunology 1998; 39: 21–27.

syndrome. Fertility & Sterility 2002; 78: 569–576.

Endocrinology & Diabetes. 2011; 119: 636-43.

1999; 14: 1563–1568.

Metabolism 1998; 83: 3078–3082.

Endocrinology 1999; 13: 946–957.

Obesity (Lond) 2009; 33:1249-56.

Endocrinology and Metabolism 2001; 86: 5925–5933.


[162] Yding Andersen C, Morineau G, Fukuda M, Westergaard LG, Ingerslev HJ, Fiet J & Byskov AG. Assessment of the follicular cortisol:cortisone ratio. Human Reproduction 1999; 14: 1563–1568.

156 Dehydrogenases

2000; 32: 142-146.

activity and LH-stimulated testosterone production. Hormone & Metabolism Research

[148] Morita H, Cozza EN, Zhou MY, Gomez-Sanchez EP, Romero DG, Gomez-Sanchez CE. Regulation of the 11 beta-hydroxysteroid dehydrogenase in the rat adrenal. Decrease

[149] Shimojo M, Condon J, Whorwood CB, Stewart PM. Adrenal 11 beta-hydroxysteroid

[150] Shimojo M, Whorwood CB, Stewart PM. 11 beta-hydroxysteroid dehydrogenase in the

[151] Smith RE, Li KX, Andrews RK, Krozowski Z. Immunohistochemical and molecular characterization of the rat 11 beta-hydroxysteroid dehydrogenase type II enzyme.

[152] Koeva YA, Bakalska MV, Petrova EI, Atanassova NN. 11beta hydroxysteroid dehydrogenase type 2 in the adrenal gland by testosterone withdrawal of adult rats.

[153] Atanassova N, Koeva Y, Bakalska M, Pavlova E, Nikolov B, Davidoff M. Loss and recovery of androgen receptor protein expression in the adult rat testis following androgen withdrawal by ethane dimethanesulfonate. Folia Histochemica et

[154] Plecas B, Pesic VP, Mirkovic D, Majkic-Singh N, hristic M, Solarovic T. Opposite effects of dexamethasone and ACTH on the adrenal cortex response to ethane dimethanesulphonate (EDS). Experimenatal Toxicology & Pathology 2001; 53: 31-34. [155] Petrova E, Koeva Y, Bakalska M, Atanassova N, Davidoff M. Morphofunctional characteristics of rat adrenocorticocytes after treatment with ethane dimethanesulphonate. Jubilee Scientific Session of Medical University, Plovdiv, 2005,

[156] Stalvey JR. Inhibition of 3 beta-hydroxysteroid dehydrogenase- isomerase in mouse

[157] Michael AE & Cooke BA. A working hypothesis for the regulation of steroidogenesis and germ cell development in the gonads by glucocorticoids and 11β-hydroxysteroid dehydrogenase (11β-HSD). Molecular and Cellular Endocrinology 1994; 100: 55–63. [158] Omura T & Morohashi K. Gene regulation of steroidogenesis. Journal of Steroid

[159] Monder C & Lakshmi V. Evidence for kinetically distinct forms of corticosteroid 11βhydroxysteroid dehydrogenase in rat liver microsomes. Journal of Steroid Biochemistry

[160] Mercer W, Obeyeskere V, Smith R & Krozowski Z. Characterization of 11βHSD1B gene expression and enzyme activity. Molecular and Cellular Endocrinology 1993; 92:

[161] Yding Andersen C. Possible new mechanism of cortisol action in female reproductive organs: physiological implications of the free hormone hypothesis. Journal of

adrenal cells: a different effect of testosterone. Steroids 2002; 67: 721-31.

Biochemistry and Molecular Biology 1995; 53: 19–25.

enzymatic activity induced by ACTH.Endocrine 1997; 7: 331-5.

rat adrenal. Journal of Molecular Endocrinology 1996; 17: 121-30.

dehydrogenase. Endocrine Research 1996; 22:771-80.

Endocrinology 1997; 138: 540-547.

Cytobiologica 2006; 44: 81-86.

abstract book; 164.

1989; 32: 77–83.

Endocrinology 2002; 173: 211–217.

247–251.

Folia Medica (Plovdiv) 2010; 52: 38-42.


steroid production rates. Journal of Clinical Endocrinology and Metabolism 2003; 88: 5907-13.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 159

[189] Walker B, Seckl J. Cortisol metabolism. In: Bjo¨rntorp P, ed. International Textbook of

[190] Morton NM, Seckl JR. 11beta-hydroxysteroid dehydrogenase type 1 and obesity.

[191] Livingstone DEW, Jones G, Smith K, Jamieson PM, Andrew R, Kenyon CJ, Walker BR. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 2000; 141: 560–563. [192] Westerbacka J, Yki-Ja¨rvinen H, Vehkavaara S, Ha¨kkinen A, Andrew R, Wake D, Seckl J, Walker B. Body fat distribution and cortisol metabolism in healthy men: enhanced 5-reductase and lower cortisol/cortisone metabolite ratios in men with fatty

liver. Journal of Clinical Endocrinology and Metabolism 2003; 88: 4924–4931.

[193] Livingstone DEW, Kenyon CJ, Walker BR. Mechanisms of dysregulation of 11 beta hydroxysteroid dehydrogenase type 1 in obese Zucker rats. Journal of Endocrinol 2000;

[194] Mattsson C, Olsson T. Estrogens and glucocorticoid hormones in adipose tissue

[195] Andersson T, Söderström I, Simonyté K, Olsson T. Estrogen reduces 11betahydroxysteroid dehydrogenase type 1 in liver and visceral, but not subcutaneous,

[196] Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294:

[197] Masuzaki H, Yamamoto H, Kenyon CJ, Elmquist JK, Morton NM, Paterson JM, Shinyama H, Sharp MGF, Fleming S. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. Journal of Clinical Investigations,

[198] Paterson JM, Morton NM, Fievet C, Kenyon CJ, Holmes MC, Staels B, Seckl JR & Mullins JJ. Metabolic syndrome without obesity: hepatic overexpression of 11bhydroxysteroid dehydrogenase type 1 in transgenic mice. Proceedings of the National

[199] Kotelevtsev YV, Holmes MC, Burchell A, Houston PM, Scholl D, Jamieson PM, Best R, Brown RW, Edwards CRW, Seckl JR & Mullins. 11b-Hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity and stress. Proceedings of the National Academy of Sciences

[200] Morton NM, Holmes MC, Fievet C, Staels B, Tailleux A, Mullins JJ & Seckl JR. Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11b hydroxysteroid dehydrogenase type 1 null mice. Journal of Biological

[201] Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ & Seckl JR. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11b-hydroxysteroid dehydrogenase type 1 deficient mice. Diabetes

Obesity. 2001, Chichester, UK: John Wiley and Sons; 241–268.

metabolism. Current Medicinal Chemistry 2007; 14:2918-24.

adipose tissue in rats. Obesity (Silver Spring). 2010; 18: 470-5.

Academy of Sciences USA 2004; 101: 7088–7093.

Frontiers in Hormone Research 2008; 36: 146-64.

167: 533–539.

2166–2170.

2003; 112: 83–90.

USA,1997; 94: 14924–14929.

2004; 53: 931–938.

Chemistry, 2001; 276: 41 293–300.


[189] Walker B, Seckl J. Cortisol metabolism. In: Bjo¨rntorp P, ed. International Textbook of Obesity. 2001, Chichester, UK: John Wiley and Sons; 241–268.

158 Dehydrogenases

5907-13.

1806–1809.

steroid production rates. Journal of Clinical Endocrinology and Metabolism 2003; 88:

[177] Draper N, Walker EA, Bujalska IJ, Tomlinson JW, Chalder SM, Arlt W, Lavery GG, Bedendo O, Ray DW, Laing I, Malunowicz E, White PC, Hewison M, Mason PJ, Connell JM, Shackleton CHL, Stewart PM. Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose- 6-phosphate dehydrogenase interact to cause

[178] Phillipov G, Palermo M, Shackleton CH. Apparent cortisone reductase deficiency: a unique form of hypercortisolism. J Clin Endocrinol Metab, 1996; 81:3855–3860. [179] Rodin A, Thakkar H, Taylor NJ, Clayton R. Hyperandrogenism in polycystic ovary syndrome: evidence of dysregulation of 11β-hydroxysteroid dehydrogenase. New

[180] Gambineri A, Vicennati V, Genghini S, Tomassoni F, Pagotto U, Pasquali R, Walker BR. Genetic variation in 11beta-hydroxysteroid dehydrogenase type 1 predicts adrenal hyperandrogenism among lean women with polycystic ovary syndrome. Journal of

[181] Hines GA, Smith ER, Azziz R. Influence of insulin and testosterone on adrenocortical steroidogenesis in vitro: preliminary studies. Fertility & Sterilility 2001; 76: 730–735. [182] Andrew R, Phillips DIW, Walker BR. Obesity and gender influence cortisol secretion and metabolism in man. Journal of Clinical Endocrinology and Metabolism 1998; 83:

[183] San Milla´n JL, Botella-Carretero JI, Alvarez-Blasco F, Luque-Ram´rez M, Sancho J, Moghetti P, Escobar-Morreale HF. A study of the hexose-6-phosphate dehydrogenase gene R453Q and 11β-hydroxysteroid dehydrogenase type 1 gene 83557insA polymorphisms in the polycystic ovary syndrome. Journal of Clinical Endocrinology

[184] White PC. Genotypes at 11β-hydroxysteroid dehydrogenase type 11B1 and hexose-6 phosphate dehydrogenase loci are not risk factors for apparent cortisone reductase deficiency in a large population-based sample. Journal of Clinical Endocrinology and

[185] Draper N, Powell BL, Franks S, Conway GS, Stewart PM & McCarthy MI. Variants implicated in cortisone reductase deficiency do not contribute to susceptibility to common forms of polycystic ovary syndrome. Clinical Endocrinology 2006; 65: 64– 70. [186] Gambineri A, Tomassoni F, Munarini A, Stimson RH, Mioni R, Pagotto U, Chapman KE, Andrew R, Mantovani V, Pasquali R, Walker BR. A combination of polymorphisms in HSD11B1 associates with in vivo 11{beta}-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome. European Journal of

[187] Mlinar B, Marc J, Jensterle M, Bokal EV, Jerin A, Pfeifer M. Expression of 11βhydroxysteroid dehydrogenase type 1 in visceral andsubcutaneous adipose tissues of patients with polycystic ovary syndrome is associated with adiposity. Journal of

[188] Reaven G. Metabolic syndrome — pathophysiology and implications for management

Steroid Biochemistry & Molecular Biology 2011; 123: 127-32.

of cardiovascular disease. Circulation 2002; 106: 286–288.

cortisone reductase deficiency. Nature Genetics 2003; 34: 434–439.

English Journal of Medicine 1994; 330: 460–465.

and Metabolism 2005; 90: 4157–4162.

Metabolism 2005; 90: 5880–5883.

Endocrinology 2011; 165: 283-92.

Clinical Endocrinology and Metabolism 2006; 91: 2295-302.


[202] Stimson RH, Walker BR. Glucocorticoids and 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. Minerva Endocrinology 2007; 32: 141- 159.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 161

[213] Morton NM. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Molecular & Cellular Endocrinology 2010 25;

[214] Morton NM, Ramage L & Seckl JR. Down-regulation of adipose 11b-hydroxysteroid dehydrogenase type 1 by high-fat feeding in mice: a potential adaptive mechanism

[215] Harris A, Seckl J. Glucocorticoids, prenatal stress and the programming of disease.

[216] Marciniak B, Patro-Małysza J, Poniedziałek-Czajkowska E, Kimber-Trojnar Z, Leszczyńska-Gorzelak B, Oleszczuk J. Glucocorticoids in pregnancy. Current

[217] McTernan CL, Draper N, Nicholson H, Chalder SM, Driver P, Hewison M, Kilby MD, Stewart PM. Reduced placental 1β-hydroxysteroid dehydrogenase type 2 mRNAlevels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. Journal of Clinical Endocrinology & Metabolism 2001; 86: 4979–

[218] Beitens IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone

[219] Brown RW, Diaz R, Robson AC, Kotelevtsev Y, Mullins JJ, Kaufman MH, Seckl JR. Isolation and cloning of human placental 11β hydroxysteroid dehydrogenase-2 cDNA.

[220] Benediktsson R, Calder AA, Edwards CRW, Seckl JR. Placental 11β-hydroxysteroid dehydrogenase type 2 is the placental barrier to maternal glucocorticoids: ex vivo

[221] Seckl JR, Holmes MC. Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology. Nat Clinical Practice of

[222] Edwards CRW, Benediktsson R, Lindsay R, Seckl JR. Dysfunction of the placental glucocorticoid barrier: a link between the foetal environment and adult hypertension?

[223] Stewart PM, Rogerson FM, Mason JI. Type 2 11β-hydroxysteroid dehydrogenase messenger RNA and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal steroidogenesis. Journal of Clinical

[224] Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL. Reduced 11βhydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. Journal of Clinical Endocrinology &

[225] Marchais-Oberwinkler S, Henn C, Möller G, Klein T, Negri M, Oster A, Spadaro A, Werth R, Wetzel M, Xu K, Frotscher M, Hartmann RW, Adamski J. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development. Journal of Steroid Biochemistry & Molecular

counteracting metabolic disease. Endocrinology 2004;145: 2707–2712.

Hormones & Behavior 201; 59: 279-89.

Pharmacology & Biotechnology 201; 12:750-757.

Biochemical Journal 1996; 313: 1007–1017.

studies. Clinical Endocrinology 1997; 46: 161–166.

Endocrinology and Metabolism 2007; 3:479-488.

Endocrinology & Metabolism 1995; 80: 885–890.

Lancet 1993; 341: 355–357.

Metabolism 2002; 87: 1660–1668.

Biology 2011; 125: 66-82.

in pregnancy near term. Pediatric Research1997; 37: 509–519.

316: 154-64.

4983.


[213] Morton NM. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Molecular & Cellular Endocrinology 2010 25; 316: 154-64.

160 Dehydrogenases

159.

44: 681–688.

136: 701–710.

54: 872–879.

2003; 144: 4755–4762.

Experimental Medicine 2005; 202: 517–527.

Metabolism 1995; 80: 3155–3159.

[202] Stimson RH, Walker BR. Glucocorticoids and 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome. Minerva Endocrinology 2007; 32: 141-

[203] Nair S, Lee YH, Lindsay RS, Walker BR, Tataranni PA, Bogardus C, Baier LJ & Permana PA. 11Beta-hydroxysteroid dehydrogenase type 1: genetic polymorphisms are associated with type 2 diabetes in Pima Indians independently of obesity and

[204] Franks PW, Knowler WC, Nair S, Koska J, Lee YH, Lindsay RS, Walker BR, Looker HC, Permana PA, Tatarani PA, Hanson RL. Interaction between an 11bHSD1 gene variant and birth era modifies risk of hypertension in Pima Indians. Hypertension 2004;

[205] Morales MA, Carvajal CA, Ortiz E, Mosso LM, Artigas RA, Owen GI & Fardella CE. Possible pathogenetic role of 11 beta-hydroxysteroid dehydrogenase type 1 (11beta HSD1) gene polymorphisms in arterial hypertension. Revista Me´dica de Chile, 2008;

[206] Rask E, Walker BR, Soderberg S, Livingstone DE, Eliasson M, Johnson O, Andrew R, Olsson T. Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. Journal of

[207] Walker BR, Connacher AA, Lindsay RM, Webb DJ, Edwards CRW. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. Journal of Clinical Endocrinology &

[208] Andrews RC, Rooyackers O, Walker BR. Effects of the 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2

[209] Sandeep TC, Andrew R, Homer NZ, Andrews RC, Smith K, Walker BR. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 2005;

[210] Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, Klingström G, Larsson C, Forsgren M, Ashkzari M, Nilsson CE, Fiedler M, Bergqvist E, Ohman B, Björkstrand E, Abrahmsen LB. Selective inhibition of 11bhydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycaemic mice strains. Endocrinology

[211] Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, Le Grand CB, Li Z, Metzger JM, Mundt SS, Noonan H, Nunes CN, Olson SH, Pikounis B, Ren N, Robertson N, Schaeffer JM, Shah K, Springer MS, Strack AM, Strowski M, Wu K, Wu T, Xiao J, Zhang BB, Wright SD, Thieringer. 11b-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. Journal of

[212] Wamil M, Seckl JR. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 as a

promising therapeutic target. Drug Discovery Today 2007; 12) :504-520.

diabetes. Journal of Clinical Endocrinology & Metabolism 2003; 88: 285–291.

expression in adipocyte and muscle. Diabetologia 2004; 47: 1088–1095.

Clinical Endocrinology & Metabolism 2002; 87: 3330–3336.


[226] Vihko P, Herrala A, Harkonen P, Isomaa V, Kaija H, Kurkela R, Pulkka A. Controlof cell proliferation by steroids: the role of 17HSDs. Molecular & Cellular Endocrinology 2006; 248: 141–148.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 163

[239] Yang SY, He XY , Miller D. HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids, Molecular Genetics & Metabolism

[240] Brereton P, Suzuki T, Sasano H, Li K, Duarte C, Obeyesekere V, Haeseleer F, Palczewski K, Smith I, Komesaroff P, Krozowski Z. Pan1b (17betaHSD11)- enzymatic activity and distribution in the lung, Molecular & Cellular Endocrinology 2001; 171:

[241] Day JM, Foster PA, Tutill HJ, Parsons MF, Newman SP, Chander SK, Allan GM, Lawrence HR, Vicker N, Potter BV, Reed MJ, Purohit A. 17betahydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine therapy of hormone-

[243] Horiguchi Y, Araki M, Motojima K.17beta-hydroxysteroid dehydrogenase type 13 is a liver-specific lipid droplet-associated protein. Biochemical Biophysical Research

[244] Lukacik P, Keller B, Bunkoczi G, Kavanagh KL, Lee WK, Adamsk Ji, U. Oppermann. U Structural and biochemical characterization of human orphan DHRS10 reveals a novel cytosolic enzyme with steroid dehydrogenase activity. Biochemical Journal 2007; 402:

[245] Jansson AK, Gunnarsson C, Cohen M, Sivik T, Stal O. 17beta-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer. Cancer Research 2006; 66: 11471–

[246] Day JM, Tutill HJ, Purohit A & Reed MJ. Design and validation of specific inhibitors of 17beta-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis. Endocrine-Related Cancer 2008; 15: 665–692. [247] Day JM, Foster PA, Tutill HJ, Parsons MF, Newman SP, Chander SK, Allan GM, Lawrence HR, Vicker N, Potter BV. 7Betahydroxysteroid dehydrogenase type 1, and not type 12, is a target for endocrine therapy of hormone-dependent breast cancer.

[248] Yang SY, He XY, Schulz H. Multiple functions of type 10 17betahydroxysteroid

[249] Vihko P, Herrala A, Harkonen P, Isomaa V, Kaija H, Kurkela R, Pulkka A. Control of cell proliferation by steroids: the role of 17HSDs. Molecular & Celular Endocrinoogy

[250] Vihko P, Herrala A, Harkonen P, Isomaa V, Kaija H, Kurkela R, Li Y, Patrikainen L, Pulkka A, Soronen P, Torn S. Enzymes as modulators in malignant transformation.

[251] Peltoket H, Luu-The V, Simard J, Adamski J. 17β-Hydroxysteroid dehydrogenase (HSD)/17-ketosteroidreductase (KSR) family; nomenclature and maincharacteristics of

the 17HSD/KSR enzymes. Journal of Molecular Endocrinology 1999; 23: 1-11.

Dehydrogenase. Trends in Endocrinoogy & Metabolism 2005; 6: 167–175.

Journal of Steroid Biochemistry & Molecular Biology 2005; 93: 277–283.

dependent breast cancer. International Journal of Cancer 2008; 122: 1931–1940. [242] Luu-The V, Tremblay P, Labrie F. Characterization of type 12 17betahydroxysteroid dehydrogenase (17beta-HSD12), an isoform of type 3 17beta-hydroxysteroid dehydrogenase responsible for estradiol formation in women. Molecular Endocrinology

2007; 92: 36–42.

2006; 20: 437–443.

419–427.

11477.

2006; 248: 141–148.

Communications 2008; 370: 35–238.

International Journal of Cancer; 2008 122: 1931–1940.

111–117.


[239] Yang SY, He XY , Miller D. HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids, Molecular Genetics & Metabolism 2007; 92: 36–42.

162 Dehydrogenases

2006; 248: 141–148.

16: 1790–1801.

270: 25213–25219.

Genetetics 2008; 82: 432–443.

[226] Vihko P, Herrala A, Harkonen P, Isomaa V, Kaija H, Kurkela R, Pulkka A. Controlof cell proliferation by steroids: the role of 17HSDs. Molecular & Cellular Endocrinology

[227] Vihko P, Herrala A, Harkonen P, Isomaa V, Kaija H, Kurkela R, Li Y, Patrikainen L, Pulkka A, Soronen P, Torn S. Enzymes as modulators in malignant transformation.

[228] Geissler W, Davis D, Wu L, Bradshaw K, Patel S, Mendonca B, Elliston K, Wilson J, Russell D, Andersson S. Male pseudohermaphroditism caused bymutations of testicular

[229] Rasiah KK, Gardiner-Garden M, Padilla FJ, Moller G, Kench JG, Alles MC, Eggleton SA, Stricker PD, Adamski J, Sutherland RL, Henshall SM, Hayes VM. HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer.

[230] Jin Y, Penning TM. Aldo–keto reductases and bioactivation/detoxication, Annual

[231] Stanbrough M, Bubley GJ, Ros K, Golub TR, Rubi MA, Penning TM, Febbo PG, Balk. SP. Increased expression of genes converting adrenal androgens to testosterone in

[233] Prehn C, Moller G, Adamski J. Recent advances in 17beta-hydroxysteroid Dehydrogenases. Journal of Steroid Biochemistry & Molecular Biology 2009; 114, 72–77. [234] Haynes BP, Straume AH, Geisler J, A'Hern R, Helle H, Smith IE, Lønning PE, Dowsett M. Intratumoral estrogen disposition in breast cancer, Clinical Cancer Research 2010;

[235] Fomitcheva J, Baker ME, Anderson E, Lee GY, Aziz N. Characterization of Ke 6, a new17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues.

[236] Maxwell MM, Nearing J, Aziz N. Ke 6 gene. Sequence and organization and aberrant regulation in murine polycystic kidney disease, Journal of Biological Chemistry 1995;

[237] Su J, Lin M, Napoli JL. Complementary deoxyribonucleic acid cloning and enzymatic characterization of a novel 17beta/3alpha-hydroxysteroid/retinoid short chain

[238] Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, Bauters M, Govaerts K, Vandeleur L, Esch H, Chelly J, Sanlaville D, Bokhoven H, Ropers HH, Laumonnier F, Ranieri E, Schwartz CE, Abidi F, Tarpey PS, Futreal PA, Whibley A, Raymond FL, Stratton MR, Fryns JP, Scott R, Peippo M, Sipponen M, Partington M, Mowat D, Field M, Hackett A, Marynen P, Turner G, Gecz J. Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation. American Journal of Human

androgen independent prostate cancer. Cancer Research 2006; 66: 2815–2825. [232] Biswas MG, Russell DW. Expression cloning and characterization of oxidative 17betaand 3alpha-hydroxysteroid dehydrogenases from rat and human prostate. Journal of

Journal of Steroid Biochemistry & Molecular Biology 2005; 93: 277–283.

17β-hydroxysteroid dehydrogenase 3, Nature Genetics 1994, 7: 34–39.

Molecular & Cellular Endocrinology 2009; 301: 89–96.

Bioogical Chemistry 1997; 272: 15959–15966.

Review of Pharmacology & Toxicology 2006; 47: 263–292.

Journal of Biological Chemistry 1998; 273: 22664–22671.

dehydrogenase/reductase. Endocrinology 1999; 140: 5275–5284.


[252] Geissler W, Davis D, Wu L, Bradshaw K, Patel S, Mendonca B, Elliston K, Wilson J, Russell D. Andersson S. Male pseudohermaphroditism caused by mutations of testicular 17β hydroxysteroid dehydrogenase 3. Nature Genetic 1994; 7: 34–39.

**Chapter 7** 

© 2012 Nwazue, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Dehydrogenases are a group of biological catalysts (enzymes) that mediate in biochemical reactions removing hydrogen atoms [H] instead of oxygen [O] in its oxido-reduction reactions. It is a versatile enzyme in the respiratory chain pathway or the electron transfer chain. T. Turnberg discovered this group of enzymes between1900-1922. Several dehydrogenases are present in tissues of humans, plants and micro-organisms having enormous biochemical interests. As a result of the polymorphic nature of this enzyme, it is pertinent therefore to limit our interest on the different functions of Lactate dehydrogenase in the diagnosis and treatment of malaria. Lactate dehydrogenase, an oxidoreductase [EC 1.1.1.27] exists in different forms in different tissues possessing different subunits as a multienzyme complex called isoenzyme. It is the last enzyme of the glycolytic sequence or pathway essential for ATP generation. The enzyme, 17β-Hydroxysteroid dehydrogenase exists in at least fourteen isoforms in tissues involved in the biosynthesis of estrogenic and androgenic steroids. Lactate dehydrogenase is a tetrameric enzyme, but only two distinct subunits have been found; those designated H for heart (myocardium) and M for muscle. These two subunits are combined in five different ways. The lactate dehydrogenase

Following myocardial infarction (MI), the serum levels of LDH rise within 24-28 hrs, reaching a peak by 2-3 days and return to normal in 5-10 days. Especially diagnostic is a comparison of the LDH1/LDH2 ratio. Normally, the ratio is less than 1. A reversal of the ratio is referred to as "flipped LDH". Following an acute myocardial infarction, the flipped ratio will appear in 12-24 hours and it is definitely present by 48 hours in over 80% of cases. Also important, is the fact that, persons suffering from chest pain due to angina only, will

isoenzymes, subunit compositions and major locations are shown below.

**Functions of Dehydrogenases** 

Additional information is available at the end of the chapter

**in Health and Disease** 

Nwaoguikpe Reginald Nwazue

http://dx.doi.org/10.5772/48278

not likely have LDH altered levels.

**1. Introduction** 


**Chapter 7** 
