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Steroids Receptors

Intracellular receptors (IRs) are a class of ligand- are primarily used for their anti-inflammatory and dependent transcription factors that include immunoregulatory effects to treat both acute receptors for both steroid and non-steroid inflammatory responses, such as asthma, as well hormones. Upon binding their cognate hormone, as chronic inflammatory diseases, such as these receptors homo- or hetero-dimerize and rheumatoid arthritis. They are also used in regulate gene expression through multiple various cancer chemotherapeutic regimens as a mechanisms. Ligand-bound IRs can positively palliative treatment and for certain lymphoid regulate transcription after binding to sequences malignancies because of their ability to induce within promoters containing binding sites for that apoptosis in specific immune cells. IR; negative regulation can occur by direct binding to a promoter or indirectly by binding to Aldosterone, the major mineralocorticoid, is and altering the activity of another transcription secreted from the adrenal gland and possibly factor. It is now clear that accessory coactivator other tissues. Aldosterone functions to maintain and corepressor proteins interact directly or water and electrolyte balance by acting upon the indirectly with IRs play a key role in distal tubules and collecting ducts of the kidney. transcriptional regulation. These proteins, Aldosterone antagonists, such as spironolactone, associate with the IR and influence chromatin are potassium-sparing diuretics used for the organization and/or recruitment of basal treatment of hypertension. Spironolactone also transcription factors and RNA polymerase II. The shows significant benefit in the treatment of pattern of genes modulated within a cell in congestive heart failure. response to an IR Ligand determines the ultimate effects on cell proliferation, cell differentiation Progesterone and other progestins are secreted and general cellular homeostasis. by the corpus luteum during the menstrual cycle and play a key role in the early maintenance of Steroid receptors include receptors for glucocor- the endometrial lining during pregnancy. ticoids, progestins, estrogens, androgens and Progestins, alone or in combination with mineralocorticoids. While these receptors were estrogens, are used as oral contraceptives. demonstrated to exist within cells as early as the Progestin antagonists, such as mifepristone (RU 1960s, it was not until 1984 that the first IR, the 486), can be used early in pregnancy as rat glucocorticoid receptor, was cloned and abortifacients. characterized. Since that time, the genes for all Estrogens are synthesized by the ovaries in known human steroid IRs have been cloned. premenopausal women. Estrogens function to Glucocorticoids are secreted from the adrenal maintain secondary sexual characteristics and cortex in response to adrenocorticotropic bone integrity in women. After menopause, hormone (ACTH). Glucocorticoids are primarily estrogen replacement reduces hot flashes and responsible for regulating carbohydrate, lipid and prevents significant bone loss. The estrogen protein metabolism, cardiovascular function and receptor partial agonist, tamoxifen, is widely used the immune system. In response to stress, the in treating breast cancer. The partial agonist levels of endogenous corticosteroids can rise raloxifene is also an antagonist in the breast and ten-fold. Therapeutically, synthetic corticoster- an agonist for bone, but lacks the uterotrophic oids including prednisone and dexamethasone activity of tamoxifen.

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The molecular basis for these differences upon functions to support sexual differentiation, selective cofactor recruitment by ER bound to spermatogenesis and has significant anabolic these selective ER modulators. In addition, effects on muscle and bone. Antagonists of aromatase inhibitors, which prevent the testosterone are used to treat prostate cancer. conversion of androgens to estrogen (e.g. Inhibitors of the conversion of testosterone to anastrozole, letrozole, and exemestane) are also dihydrotestosterone have been used to treat used to treat ER-positive breast cancer. benign prostatic hypertrophy and may reverse male pattern baldness. Testosterone, dihydrotestosterone and other androgens are responsible for behavioral and The Table below contains accepted modulators secondary sexual characteristics of both males and additional information. For more information and females. Testosterone, synthesized de novo and a complete list of the related products, please by the testes and adrenal gland, is secreted click: Aladdin during gestation, again during the neonatal period, and throughout adulthood. Testosterone

Currently Accepted Name Estrogen receptor Glucocorticoid receptor

ERα (NR3A1) GR (NR3C1) Alternate Name a ERβ (NR3A2) GRα

Structural Information 595 aa (human) 777 aa (human)

Dexamethasone 17-β-Estradiol Triamcinolone Receptor Selective Agonists Estrone Hydrocortisone Moxestrol Prednisone

ICI 182,780 c Mifepristone (RU 486) Keoxifene c Receptor Selective Antagonists b Onapristone (ZK 98299) 4-Hydroxytamoxifen ZK 91587 Tamoxifen

Signal Transduction Modulation of gene expression by ligand-dependent transcription factors Mechanisms

[3H]-Estradiol [3H]-Hydroxycortisone Radioligands of Choice [125I]-Iodoestradiol [3H]-Deoxycorticosterone [3H]-Tamoxifen [3H]-Dexamethasone

Ovary Tissue Expression Pituitary Ubiquitous Uter us

Regulation of carbohydrate, lipid, and protein Maintenance of female reproductive Physiological Function metabolism system Regulation of cardiovascular and immune function

Osteoporosis Asthma Disease Relevance Cancer Arthritis Pregnancy prevention Cancer

Currently Progesterone receptor Androgen receptor Mineralocorticoid Accepted Name receptor

PRβ (NR3C3) Alternate Name d AR (NR3C4) MR (NR3C2) PRα

Structural 933 aa (human) 919 aa (human) 984 aa (human) Information

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Testosterone Progesterone Stanolone Receptor Norethynodrel Oxymetholone Selective Medroxyprogesterone Oxandrolone Aldosterone Agonists R5020 Methyltrienolone Iodovinylnortestosterone Fluoxymesterone Androstenedione

Bicalutamide Receptor c e Mifepristone (RU 486) 2-Hydroxyflutamide Spironolactone Selective c Onapristone (ZK 98299) Nilutamide Eplerenone Antagonists f Cyproterone acetate

Signal Transduction Modulation of gene expression by ligand-dependent transcription factors Mechanisms

125 3 [ I]-Iodovinylnortestosterone [ H]-Dihydrotestosterone 3 Radioligands of 3 3 [ H]-Aldosterone [ H]-Progesterone [ H]-Methyltrienolone 3 Choice 3 3 [ H]-Spironolactone [ H]-R5020 [ H]-Testosterone

Adrenal, brain, epididymus, Brain, colon, kidney, Tissue Uterus, brain, hypothalmus, ovary, spinal hypothalamus, kidney, muscle, pituitary, skin, spinal Expression cord ovary, pituitary, prostate, skin, cord, thyroid, heart uterus, adipose tissue

Establishment and maintenance of pregnancy Proper development and function of Regulation of electrolyte Physiological Breast development male reproductive organs and fluid balance Function Sexual behavior Anabolic action Specific CNS roles

Prostate cancer Disease Congestive heart failure Pregnancy prevention and termination Osteoporosis Relevance Blood pressure Frailty

Footnotes analogues with the human glucocorticoid receptor., J. a) A second GR isoform (GRβ) has been Steroid Biochem. Mol. Biol., 41, 733-738 (1992). identified. GRβ contains 742 amino acids, does Bryant, DN. and Dorsa, DM., Roles of estrogen receptors alpha and beta in sexually dimorphic not bind glucocorticoids and has been shown to neuroprotection against glutamate toxicity., be a dominant-negative mutant. Neuroscience., 170, 1261-1269 (2010). b) Tissue-specific antagonist. Evans, R.M., The steroid and thyroid hormone c) Potent antiglucocorticoid and antiprogestin receptor superfamily., Science, 240, 889-895 (1988). with weaker potency as an antagonist on the Funder, J.W., Glucocorticoid and mineralcorticoid androgen receptor. receptors biology and clinical relevance., Annu. Rev. d) PRα and PRβ are identical except for alternate Med., 48, 231-240 (1997). splicing of amino terminal. PRβ is approximately Glass, C.K. and Rosenfeld, M.G., The coregulator 22 kDa larger. The pharmacological differences exchange in transcriptional functions of nuclear are not fully understood. receptors., Genes Dev., 14, 121-141 (2000). Jonat, C., et al., Antitumor promotion and e) Active metabolite of flutamide. antiinflammation: Down-modulation of AP-1 (fos/jun) f) Also a progesterone agonist. activity by glucocorticoid hormone., Cell, 62, 1189- 1204 (1990). AbbreviationsF Koch, H., Flutamide - A new non-steroidal anti- ICI 182,780: 7α-[9-(4,4,5,5,5-Pentafluoro- androgen., Drugs of Today, 20, 561-574 (1984). pentylsulphinyl)nonyl]oestra-1,3,5(10)-triene- Manna, PR., et al., Mechanisms of action of hormone- 3,17β-diol sensitive lipase in mouse Leydig cells: its role in the R5020: 17,21-Dimethyl-19-nor-4,9-pregnadiene- regulation of the steroidogenic acute regulatory 3,20-dione protein., J Biol Chem., 288, 8505-8518 (2013). McDonnell, D.P., The molecular pharmacology of

SERMs., Trends Endocrinol. Metab., 10, 301-311 References (1999). Bensinger, SJ. and Tontonoz, P. Integration of Miesfeld, R., et al., Characterization of a steroid metabolism and inflammation by lipid-activated hormone receptor gene and mRNA in wild-type and nuclear receptors., Nature., 7203, 470-477 (2008). mutant cells., Nature, 312, 779-781 (1984). Berger, T.S., et al., Interaction of glucocorticoid Pitt, B., et al., The effect of spironolactone on

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www.aladdin-e.com morbidity and mortality in patients with severe heart Eng. J. Med., 329, 404-412 (1993). failure., New Eng. J. Med., 341, 709-717 (1999). Zelcer, N., et al., LXR regulates cholesterol uptake Prinz, G.S., Molecular biology of the androgen through Idol-dependent ubiquitination of the LDL receptor., Mayo Clin. Proc., 75, Suppl. S32-35 (2000). receptor., Science., 325, 100-104 (2009). Shang, Y. and Brown, M., Molecular determinants for the tissue specificity of SERMs., Science, 295, 2465- For more information and a complete list of the 2468 (2002). related products, please click: Aladdin Spitz, I.M. and Bardin, C.W., Mifepristone (RU 486) - a modulator of progestin and glucocortoid action., New

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