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DOI: 10.1055/s-2004-861552
Adrenal Androgens and Aging
Publication History
Publication Date:
05 January 2005 (online)
ABSTRACT
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are the principal C19 steroids produced by the human adrenals. Their plasma levels decline to less than 20% of their maximal value during aging. Because these steroids appear to play a role in the maintenance of immunity, musculoskeletal integrity, and cardiovascular health, age-associated declines in adrenal androgen production may contribute to decreased immune function, osteoporosis, and atherosclerosis. Production of DHEA and DHEAS has been localized to the zona reticularis (ZR) of the adrenal cortex and can be modulated by intra-adrenal or extra-adrenal modulators. Extra-adrenal modulators include corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), insulin, and transforming growth factor β (TGF-β). Intra-adrenal regulators include enzymes and proteins involved in the steroidogenic pathway, specifically 17,20 lyase activity and DHEA sulfotransferase (DST). The natural histories of the emergence of adrenal androgen production and the ontogeny of the ZR appear to correlate closely. In addition, aging results in a decline in adrenal androgen production, and our data suggest a parallel diminution in the area represented by the ZR. This decline in the ZR may result from apoptosis, cellular and humoral immunity, or a reduction in the replicative capacity of the cells of the ZR.
KEYWORDS
Adrenal cortex - aging - androgens - zona reticularis - DHEA - DHEAS
REFERENCES
- 1 Cooke B A, Vanha-Perttula T, Klopper A. Steroid biosynthesis in vitro by 6-8 week human foetal adrenal glands. Scand J Clin Lab Invest. 1968; 21 30
- 2 Labrie F, Belanger A, Luu-The V et al.. DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids. 1998; 63 322-328
- 3 Judd H L, Judd L E, Lucas W E, Yen S S. Endocrine function of postmenopausal ovaries: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab. 1974; 39 1020-1024
- 4 Rosenfeld R S, Rosenberg B J, Fukushira O K, Hellman L. 24-h secretory pattern of dehydroepiandrosterone and dehydroepiandrosterone sulfate. J Clin Endocrinol Metab. 1975; 40 850-855
- 5 Parker Jr C R, Leveno K, Carr B R, Hauth J, MacDonald P C. Umbilical cord plasma levels of dehydroepiandrosterone sulfate during human gestation. J Clin Endocrinol Metab. 1982; 54 1216-1220
- 6 Siiteri P K, MacDonald P C. Placental estrogen biosynthesis during human pregnancy. J Clin Endocrinol Metab. 1966; 26 751-761
- 7 Migeon C J, Keller A R, Lawrence B, Shepard T H. Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex; day-to-day and diurnal variations. J Clin Endocrinol Metab. 1957; 17 1051-1062
- 8 Parker L N. Control of adrenal androgen secretion. Endocrinol Metab Clin North Am. 1991; 20 401-421
- 9 Parker Jr C R. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids. 1999; 64 640-647
- 10 Azziz R, Fox L M, Zacur H A, Parker Jr C R, Boots L R. Adrenocortical secretion of dehydroepiandrosterone in healthy women: highly variable response to adrenocorticotropin. J Clin Endocrinol Metab. 2001; 86 2513-2517
- 11 Isojarvi J, Pakarinen A, Ylipalosaari P, Myllyla V. Serum hormones in male epileptic patients receiving anticonvulsant medications. Arch Neurol. 1990; 47 670-678
- 12 Bhathena S, Berlin E, Judd J et al.. Hormones regulating lipid and carbohydrate metabolism in premenopausal women: modulation by dietary lipids. Am J Clin Nutr. 1989; 49 752-757
- 13 Khaw K, Tazuke S, Barrett-Conner E. Cigarette smoking and levels of adrenal androgens in postmenopausal women. N Engl J Med. 1988; 318 1705-1709
- 14 Labrie F, Belanger A, Cusan L, Gomez J L, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 1997; 82 2396-2402
- 15 Burger H G, Dudley E C, Cui J, Dennerstein L, Hopper J L. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab. 2000; 85 2832-2838
- 16 Parker Jr C R, Slayden S, Azziz R et al.. Effects of aging on adrenal function in the human: responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women. J Clin Endocrinol Metab. 2000; 85 48-54
- 17 Vermeulen A, Deslypere J P, Schelfhout W, Verdonck L, Rubens R. Adrenocortical function in old age: response to acute adrenocorticotropin stimulation. J Clin Endocrinol Metab. 1982; 54 187-191
- 18 Liu C H, Laughlin G A, Fischer U G, Yen S SC. Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20 desmolase enzymatic activity. J Clin Endocrinol Metab. 1990; 71 900-906
- 19 Longcope C. The metabolism of dehydroepiandrosterone sulfate. Semin Reprod Endocrinol. 1995; 13 270-274
- 20 Sapolsky R M, Vogelman J H, Orentreich N, Altmann J. Senescent decline in serum dehydroepiandrosterone sulfate concentrations in a population of wild baboons. J Gerontol. 1993; 48 B196-B200
- 21 Lane M A, Ingram D K, Ball S S, Roth G S. Dehydroepiandrosterone sulfate. A biomarker of primate aging slowed by calorie restriction. J Clin Endocrinol Metab. 1997; 82 2093-2096
- 22 Davis S R, Burger H G. Androgens and the postmenopausal woman. J Clin Endocrinol Metab. 1996; 81 2759-2763
- 23 Schwartz A G, Pashko L, Whitcomb J M. Inhibition of tumor development by dehydroepiandrosterone and related steroids. Toxicol Pathol. 1986; 14 357-362
- 24 Lucas J A, Ahmed S A, Casey M L, MacDonald P C. Prevention of autoantibody formation and prolonged survival in New Zealand black/New Zealand white F1 mice fed dehydroepiandrosterone. J Clin Invest. 1985; 75 2091-2093
- 25 Meikle A W, Daynes R A, Araneo B A. Adrenal androgen secretion and biologic effects. Endocrinol Metab Clin North Am. 1991; 20 381-399
- 26 Flood J F, Roberts E. Dehydroepiandrosterone sulfate improves memory in aging mice. Brain Res. 1988; 448 178-181
- 27 Sunderland T, Merril C R, Harrington M G. Reduced plasma dehydroepiandrosterone concentrations in Alzheimer's disease. Lancet. 1989; 2 570
- 28 Schneider L S, Hinsey M, Lyness S. Plasma dehydroepiandrosterone sulfate in Alzheimer's disease. Biol Psychiatry. 1992; 31 205-208
- 29 Notelovitz M. Androgen effects on bone and muscle. Fertil Steril. 2002; 77 S34-S41
- 30 Luo S, Labrie C, Belanger A, Labrie F. Effect of dehydroepiandrosterone on bone mass, serum lipids, and dimethylbenz(a)anthracene-Induced mammary carcinoma in the rat. Endocrinology. 1997; 138 3387-3394
- 31 Bachmann G A. The hypoandrogenic woman: pathophysiologic overview. Fertil Steril. 2002; 77 S72-S76
- 32 Dimitrakakis C, Zhou J, Bondy C A. Androgens and mammary growth and neoplasia. Fertil Steril. 2002; 77 S26-S33
- 33 Hollo I, Feher T, Szucs J. Serum dehydroepiandrosterone, androsterone and cortisol level in primary postmenopausal and other type osteoporosis. Acta Med Acad Sci Hung. 1970; 27 155-160
- 34 Loria R M, Inge T H, Cook S S, Szakal A K, Regelson W. Protection against acute lethal viral infections with the native steroid dehydroepiandrosterone (DHEA). J Med Virol. 1988; 26 301-134
- 35 Pashko L, Schwartz A, Abou-Gharbia M et al.. Inhibition of DNA synthesis in mouse epidermis and breast epithelium by DHEA and related steroids. Carcinogenesis. 1981; 2 717-721
- 36 Barrett-Conner E, Khaw K T, Yen S SC. A prospective study of dehydroepiandrosterone sulfate, mortality and cardiovascular disease. N Engl J Med. 1986; 315 1519-1524
- 37 Herrington D M, Gordon G B, Achuff S C et al.. Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography. J Am Coll Cardiol. 1990; 16 862-870
- 38 Kimura M, Tanaka S, Yamada Y et al.. Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats. Endocrinology. 1998; 139 3249-3253
- 39 Gordon G B, Bush D E, Weisman H F. Reduction of atherosclerosis by administration of dehydroepiandrosterone. A study in the hypercholesteremic New Zealand white rabbit with aortic intimal injury. J Clin Invest. 1988; 82 712-720
- 40 Nestler J E, Clore J N, Blackard W G. Dehydroepiandrosterone: the “missing link” between hyperinsulinemia and atherosclerosis?. FASEB J. 1992; 6 3073
- 41 Coleman D L, Leiter E H, Schwizer R W. Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice. Diabetes. 1982; 31 830-833
- 42 Shirley I M, Cooke B A. Localization of dehydroepiandrosterone sulphokinase and 3 beta-hydroxysteroid dehydrogenase-isomerase activities in the human foetal adrenal gland. J Endocrinol. 1969; 45(Suppl) xxvi+
- 43 Endoh A, Kristiansen S B, Casson P R, Buster J E, Hornsby P J. The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3-beta hydroxysteroid dehydrogenase. J Clin Endocrinol Metab. 1996; 81 3558-3565
- 44 Kennerson A R, McDonald D A, Adams J B. Dehydroepiandrosterone sulfotransferase localization in human adrenal glands: a light and electron microscopic study. J Clin Endocrinol Metab. 1983; 56 786-790
- 45 Conley A J, Bird I M. The role of cytochrome P450 17 alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase in the integration of gonadal and adrenal steroidogenesis via the delta 5 and delta 4 pathways of steroidogenesis in mammals. Biol Reprod. 1997; 56 789-799
- 46 Mapes S, Corbin C J, Tarantal A, Conley A. The primate adrenal zona reticularis is defined by the expression of cytochrome b5, 17α hydroxylase/17,20 lyase cytochrome P450 (P450C17) and NADPH-cytochrome P450 reductase but not 3 beta-hydroxysteroid dehydrogenase/Δ5-4 isomerase (3βHSD). J Clin Endocrinol Metab. 1999; 84 3382-3385
- 47 Parker Jr. C R, Jian M, Conley A J. The localization of DHEA sulfotransferase in steroidogenic and steroid metabolizing tissues of the adult rhesus macaque monkey. Endocrine Res. 2000; 26 517-522
- 48 L'Allemand D, Penhoat A, Lebrethon M C et al.. Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab. 1996; 81 3892-3897
- 49 Nestler J E, Clore J N, Strauss J F, Blackard W G. The effects of hyperinsulinemia on serum testosterone, progesterone, dehydroepiandrosterone sulfate, and cortisol levels in normal women and in a woman with hyperandrogenism, insulin resistance, and acanthosis nigricans. J Clin Endocrinol Metab. 1987; 64 180-184
- 50 Lebrethon M C, Jaillard C, Naville D, Begeot M, Saez J M. Effects of transforming growth factor-beta 1 on human adrenocortical fasciculata-reticularis cell differentiated functions. J Clin Endocrinol Metab. 1994; 79 1033-1039
- 51 Stankovic A K, Dion L D, Parker Jr C R. Effects of transforming growth factor-beta on human fetal adrenal steroid production. Mol Cell Endocrinol. 1994; 99 145-151
- 52 Lin D, Black S M, Nagahama Y, Miller W L. Steroid 17 alpha-hydroxylase and 17,20 lyase activities of p450C17: contributions of serine 106 and p450 reductase. Endocrinology. 1993; 132 2498-2506
- 53 Zhang L H, Rodriguez H, Ohno S, Miller W L. Serine phosphorylation of human p450C17 increases 17,20 lyase activity: implications for adrenarche and for the polycystic ovary syndrome. Proc Natl Acad Sci USA. 1995; 92 10619-10623
- 54 Katagiri M, Kagawa N, Waterman M R. The role of cytochrome b5 in the biosynthesis of androgens by human p450C17. Arch Biochem Biophys. 1995; 317 343-347
- 55 Lee-Robichaud P, Wright J N, Akhtar M E, Akhtar M. Modulation of the activity of human 17 alpha hydroxylase-17,20 lyase (CYP17) by cytochrome b5: endocrinological and mechanistic implications. Biochem J. 1995; 308 901-908
- 56 Auchus R J, Lee T C, Miller W L. Cytochrome b5 augments the 17,20 lyase activity of human p450C17 without direct electron transfer. J Biol Chem. 1998; 273 3158-3165
- 57 Dharia S P, Slane A, Jian M et al.. Co-localization of p450C17 and cytochrome b5 in androgen synthesizing tissues of the human. Biol Reprod. 2004; 71 83-88
- 58 Rainey W E, Carr B R, Sasano H, Suzuki T, Mason J I. Dissecting human adrenal androgen production. Trends Endocrinol Metab. 2002; 13 234-239
- 59 Suzuki T, Sasano H, Takeyama J et al.. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies. Clin Endocrinol. 2000; 53 739-747
- 60 Sakai Y, Yanase T, Takayanagi R et al.. High expression of cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome associated with high secretion of adrenal androgens. J Clin Endocrinol Metab. 1993; 76 1286-1290
- 61 Yanase T, Sasano H, Yubisui T et al.. Immunohistochemical study of cytochrome b5 in human adrenal gland and in adrenocortical adenomas from patients with Cushing's syndrome. Endocr J. 1998; 45 89-95
- 62 Parker Jr. C R, Mixon R L, Brissie R M, Grizzle W E. Aging alters zonation in the adrenal cortex of men. J Clin Endocrinol Metab. 1997; 82 3898-3901
- 63 Kreiner E, Dhom G. Age-related changes of the human adrenal gland [author's transl; in German]. Zentralbl Allg Pathol. 1979; 123 351-360
- 64 Parker L N, Lifrak E T, Mamadan M B, Lai M K. Aging and the human zona reticularis. Arch Androl. 1983; 10 17-20
- 65 Dharia S P, Slane A, Conner M G, Parker Jr C R. Reduced Cytochrome b5: Cause for Adrenal Androgen Deficiency in Aging Women?. Proceedings of the 2003 Endocrine Society Annual Meeting June 26, 2003 Philadelphia, PA; Abstract #OR17-3
- 66 Wolkersdorfer G W, Ehrhart-Bornstein M, Brauer S et al.. Differential regulation of apoptosis in the normal human adrenal gland. J Clin Endocrinol Metab. 1996; 81 4129-4136
- 67 Spencer S J, Rabinovici J, Mesiano S, Goldsmith P C, Jaffe R B. Activin and inhibin in the human adrenal gland; regulation and differential effects in fetal and adult cells. J Clin Invest. 1992; 90 142-149
- 68 Vanttinen T, Liu J, 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; 178 479-489
- 69 Stankovic A K, Grizzle W E, Stockard C R, Parker Jr C R. Interactions between transforming growth factor β and adrenocorticotropin in growth regulation of human adrenal fetal zone cells: possible involvement of adenylate cyclase. Am J Physiol. 1994; 266 E495-E500
- 70 Spencer S J, Mesiano S, Lee J Y, Jaffe R B. Proliferation and apoptosis in the human adrenal cortex during the fetal and perinatal periods: implications for growth and remodeling. J Clin Endocrinol Metab. 1999; 84 1110-1115
- 71 Hinshaw L B. Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med. 1996; 24 1072-1078
- 72 Khoury E L, Berline J W. HLA-DR expression by adrenocortical cells of the zona reticularis: structural and allotypic characterization. Tissue Antigens. 1988; 31 191-203
- 73 Marx C, Bornstein S R, Wolkersdorfer G W et al.. Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex. J Clin Endocrinol Metab. 1997; 82 3136-3140
- 74 Hayashi Y, Hiyoshi T, Takemura T, Kurashima C, Hirokawa K. Focal lymphocytic infiltration in the adrenal cortex of the elderly: immunohistochemical analysis of infiltrating lymphocytes. Clin Exp Immunol. 1989; 77 101-105
- 75 Hornsby P J. Aging of the human adrenal cortex. Ageing Res Rev. 2002; 1 229-242
- 76 Yang L, Suwa T, Wright W E, Shay J W, Hornsby P J. Telomere shortening and decline in replicative potential as a function of donor age in human adrenocortical cells. Mech Ageing Dev. 2001; 122 1685-1694
C. Richard Parker Jr.Ph.D.
Professor, Department of Obstetrics and Gynecology, University of Alabama at Birmingham
618 South 20th Street, 360 Old Hillman Building
Birmingham, AL 35294-7333
Email: crparker@uab.edu