Semin Reprod Med 2004; 22(4): 337-347
DOI: 10.1055/s-2004-861550
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

The Rise in Adrenal Androgen Biosynthesis: Adrenarche

Jon C. Havelock1 , Richard J. Auchus2 , William E. Rainey1
  • 1Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology
  • 2Division of Endocrinology and Metabolism, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas
Further Information

Publication History

Publication Date:
05 January 2005 (online)

ABSTRACT

Adrenarche is characterized by the increase in adrenal androgen production, namely dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) that occurs around 6 years of age. These steroids are secreted by the zona reticularis (ZR) of the adrenal gland. This is associated with pubarche or the increase in androgen-dependent hair growth at the time of puberty. The increase in adrenal androgen production can be explained by the increase in the expression of DHEA-synthesizing steroidogenic enzymes in the ZR. Adrenarche is an event independent of gonadarche and is found only in humans and select nonhuman primates. Although numerous prenatal and postnatal factors are important in the onset of adrenarche, a specific adrenal cortical androgen-stimulating hormone has not been identified. Evidence also exists for a role for adrenarche in behavior, skeletal maturation, and postpubertal well-being. Adrenarche is influenced by sex and race, and some of this variation may be related to the insulin and insulin-like growth factor (IGF) signaling pathways. In addition, children with premature and exaggerated adrenarche may be predisposed to certain diseases later in life.

REFERENCES

  • 1 Albright F, Smith P H, Fraser R. A syndrome characterized by primary ovarian insufficiency and decreased stature: report of 11 cases with a digression on hormonal control of axillary and pubic hair.  Am J Med Sci. 1942;  204 625-648
  • 2 Reiter E O, Fuldauer V G, Root A W. Secretion of the adrenal androgens dehydroepiandrosterone sulfate during normal infancy, childhood, and adolescence, in sick children and in children with endocrinologic abnormalities.  J Pediatr. 1977;  90 766-770
  • 3 Ducharme J R, Forest M G, De Peretti E et al.. Plasma adrenal and gonadal sex steroids in human pubertal development.  J Clin Endocrinol Metab. 1976;  42 468-476
  • 4 Sizonenko P C, Paunier L. Hormonal changes in puberty III: correlation of plasma dehydroepiandrosterone, testosterone, FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with premature or late adrenarche.  J Clin Endocrinol Metab. 1975;  41 894-904
  • 5 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
  • 6 Ibanez L, Dimartino-Nardi J, Potau N, Saenger P. Premature adrenarche-normal variant or forerunner of adult disease?.  Endocr Rev. 2000;  21 671-696
  • 7 Cutler Jr G B, Glenn M, Bush M et al.. Adrenarche: a survey of rodents, domestic animals, and primates.  Endocrinology. 1978;  103 2112-2118
  • 8 Schiebinger R J, Albertson B D, Barnes K M, Cutler Jr G B, Loriaux D L. Developmental changes in rabbit and dog adrenal function: a possible homologue of adrenarche in the dog.  Am J Physiol. 1981;  240 E694-E699
  • 9 Smail P J, Faiman C, Hobson W C, Fuller G B, Winter J S. Further studies on adrenarche in nonhuman primates.  Endocrinology. 1982;  111 844-848
  • 10 Siiteri P K, MacDonald P C. Placental estrogen biosynthesis during human pregnancy.  J Clin Endocrinol Metab. 1966;  26 751-761
  • 11 Compagnone N A, Mellon S H. Dehydroepiandrosterone: a potential signalling molecule for neocortical organization during development.  Proc Natl Acad Sci USA. 1998;  95 4678-4683
  • 12 Parker L N. Adrenarche.  Endocrinol Metab Clin North Am. 1991;  20 71-83
  • 13 Sklar C A, Kaplan S L, Grumbach M M. Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence.  J Clin Endocrinol Metab. 1980;  51 548-556
  • 14 Arlt W, Callies F, van Vlijmen J C et al.. Dehydroepiandrosterone replacement in women with adrenal insufficiency.  N Engl J Med. 1999;  341 1013-1020
  • 15 Lathe R. Steroid and sterol 7-hydroxylation: ancient pathways.  Steroids. 2002;  67 967-977
  • 16 Baker M E. Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors.  Mol Cell Endocrinol. 2004;  215 55-62
  • 17 Baker M E. Steroid receptor phylogeny and vertebrate origins.  Mol Cell Endocrinol. 1997;  135 101-107
  • 18 Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu E E. Characterization and measurement of dehydroepiandrosterone sulfate in rat brain.  Proc Natl Acad Sci USA. 1981;  78 4704-4707
  • 19 Talbot N B, Butler A M, Berman R A, Rodriguez P M, MacLachan E A. Excretion of 17-ketosteroid by normal and by abnormal children.  Am J Dis Child. 1943;  65 364-375
  • 20 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
  • 21 Wierman M E, Beardsworth D E, Crawford J D et al.. Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche.  J Clin Invest. 1986;  77 121-126
  • 22 Lashansky G, Saenger P, Fishman K et al.. Normative data for adrenal steroidogenesis in a healthy pediatric population: age- and sex-related changes after adrenocorticotropin stimulation.  J Clin Endocrinol Metab. 1991;  73 674-686
  • 23 Orentreich N, Brind J L, Rizer R L, Vogelman J H. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood.  J Clin Endocrinol Metab. 1984;  59 551-555
  • 24 Stewart P M. Adrenal cortex and endocrine hypertension. In: Larsen PR Williams Textbook of Endocrinology St. Louis, MO; Elsevier 2003: 491-586
  • 25 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
  • 26 Zhang L H, Rodriguez H, Ohno S, Miller W L. Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome.  Proc Natl Acad Sci USA. 1995;  92 10619-10623
  • 27 Kagimoto M, Winter J S, Kagimoto K, Simpson E R, Waterman M R. Structural characterization of normal and mutant human steroid 17 α-hydroxylase genes: molecular basis of one example of combined 17 α-hydroxylase/17,20 lyase deficiency.  Mol Endocrinol. 1988;  2 564-570
  • 28 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
  • 29 Suzuki T, Sasano H, Takeyama J et al.. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies.  Clin Endocrinol (Oxf). 2000;  53 739-747
  • 30 Pandey A V, Mellon S H, Miller W L. Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17.  J Biol Chem. 2003;  278 2837-2844
  • 31 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
  • 32 Dharia S, Slane A, Jian M et al.. Colocalization of P450c17 and cytochrome b5 in androgen-synthesizing tissues of the human.  Biol Reprod. 2004;  71 83-88
  • 33 Labrie F, Simard J, Luu-The V et al.. Structure and tissue-specific gene expression of 3β-hydroxysteroid dehydrogenase/5-ene-4-ene isomerase genes in human and rat classical and peripheral steroidogenic tissues.  J Steroid Biochem Mol Biol. 1992;  41 421-435
  • 34 Conley A J, Bird I M. The role of cytochrome P450 17 α-hydroxylase and 3 β-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
  • 35 Goldman A S, Yakovac W C, Bongiovanni A M. Development of activity of 3β-hydroxysteroid dehydrogenase in human fetal tissues and in two anencephalic newborns.  J Clin Endocrinol Metab. 1966;  26 14-22
  • 36 Simonian M H, Capp M W. Characterization of steroidogenesis in cell cultures of the human fetal adrenal cortex: comparison of definitive zone and fetal zone cells.  J Clin Endocrinol Metab. 1984;  59 643-651
  • 37 Dardis A, Saraco N, Rivarola M A, Belgorosky A. Decrease in the expression of the 3β-hydroxysteroid dehydrogenase gene in human adrenal tissue during prepuberty and early puberty: implications for the mechanism of adrenarche.  Pediatr Res. 1999;  45 384-388
  • 38 Gell J S, Carr B R, Sasano H et al.. Adrenarche results from development of a 3β-hydroxysteroid dehydrogenase-deficient adrenal reticularis.  J Clin Endocrinol Metab. 1998;  83 3695-3701
  • 39 Bassett M H, Suzuki T, Sasano H et al.. The orphan nuclear receptor NGFIB regulates transcription of 3β-hydroxysteroid dehydrogenase: implications for the control of adrenal functional zonation.  J Biol Chem. 2004;  279 37622-37630
  • 40 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
  • 41 Bech K, Tygstrup I, Nerup J. The involution of the foetal adrenal cortex. A light microscopic study.  Acta Pathol Microbiol Scand. 1969;  76 391-400
  • 42 Dhom G. The prepuberal and puberal growth of the adrenal (adrenarche).  Beitr Pathol. 1973;  150 357-377
  • 43 Grumbach M M, Richards H E, Conte F A et al.. Clinical disorders of adrenal function and puberty: assessment of the role of the adrenal cortex and abnormal puberty in man and evidence for an ACTH-like pituitary adrenal androgen stimulating hormone. In: James VHT, Serio M, Giusti G, et al The Endocrine Function of the Human Adrenal Cortex New York; Academic Press 1978: 583-612
  • 44 Urban M D, Lee P A, Gutai J P, Migeon C J. Androgens in pubertal males with Addison's disease.  J Clin Endocrinol Metab. 1980;  51 925-929
  • 45 Auchus R J, Rainey W E. Adrenarche-physiology, biochemistry and human disease.  Clin Endocrinol (Oxf). 2004;  60 288-296
  • 46 Ishii T, Ogata T, Sasaki G et al.. Novel mutations of the ACTH receptor gene in a female adult patient with adrenal unresponsiveness to ACTH.  Clin Endocrinol (Oxf). 2000;  53 389-392
  • 47 Weber A, Clark A J, Perry L A, Honour J W, Savage M O. Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche.  Clin Endocrinol (Oxf). 1997;  46 431-437
  • 48 Murch S H, Carter E P, Tsagarakis S, Grossman A, Savage M O. Isolated ACTH deficiency with absent response to corticotrophin-releasing factor-41. Evidence for a primary pituitary defect.  Acta Paediatr Scand. 1991;  80 259-261
  • 49 Albertson B D, Hobson W C, Burnett B S et al.. Dissociation of cortisol and adrenal androgen secretion in the hypophysectomized, adrenocorticotropin-replaced chimpanzee.  J Clin Endocrinol Metab. 1984;  59 13-18
  • 50 Mellon S H, Shively J E, Miller W L. Human proopiomelanocortin-(79-96), a proposed androgen stimulatory hormone, does not affect steroidogenesis in cultured human fetal adrenal cells.  J Clin Endocrinol Metab. 1991;  72 19-22
  • 51 Penhoat A, Sanchez P, Jaillard C, Langlois D, Begeot M, Saez J M. Human proopiomelanocortin-(79-96), a proposed cortical androgen-stimulating hormone, does not affect steroidogenesis in cultured human adult adrenal cells.  J Clin Endocrinol Metab. 1991;  72 23-26
  • 52 Smith R, Mesiano S, Chan E C, Brown S, Jaffe R B. Corticotropin-releasing hormone directly and preferentially stimulates dehydroepiandrosterone sulfate secretion by human fetal adrenal cortical cells.  J Clin Endocrinol Metab. 1998;  83 2916-2920
  • 53 Ibanez L, Potau N, Marcos M V, de Zegher F. Corticotropin-releasing hormone: a potent androgen secretagogue in girls with hyperandrogenism after precocious pubarche.  J Clin Endocrinol Metab. 1999;  84 4602-4606
  • 54 Mesiano S, Katz S L, Lee J Y, Jaffe R B. Insulin-like growth factors augment steroid production and expression of steroidogenic enzymes in human fetal adrenal cortical cells: implications for adrenal androgen regulation.  J Clin Endocrinol Metab. 1997;  82 1390-1396
  • 55 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
  • 56 Smith C P, Dunger D B, Williams A J et al.. Relationship between insulin, insulin-like growth factor I, and dehydroepiandrosterone sulfate concentrations during childhood, puberty, and adult life.  J Clin Endocrinol Metab. 1989;  68 932-937
  • 57 Guercio G, Rivarola M A, Chaler E, Maceiras M, Belgorosky A. Relationship between the GH/IGF-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal boys.  J Clin Endocrinol Metab. 2002;  87 1162-1169
  • 58 Guercio G, Rivarola M A, Chaler E, Maceiras M, Belgorosky A. Relationship between the growth hormone/insulin-like growth factor-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal girls.  J Clin Endocrinol Metab. 2003;  88 1389-1393
  • 59 Genazzani A R, Pintor C, Corda R. Plasma levels of gonadotropins, prolactin, thyroxine, and adrenal and gonadal steroids in obese prepubertal girls.  J Clin Endocrinol Metab. 1978;  47 974-979
  • 60 Pintor C, Loche S, Faedda A et al.. Adrenal androgens in obese boys before and after weight loss.  Horm Metab Res. 1984;  16 544-548
  • 61 Rolland-Cachera M F. Body composition during adolescence: methods, limitations and determinants.  Horm Res. 1993;  39 (Suppl 3) 25-40
  • 62 Remer T, Manz F. Role of nutritional status in the regulation of adrenarche.  J Clin Endocrinol Metab. 1999;  84 3936-3944
  • 63 Suter K J, Pohl C R, Wilson M E. Circulating concentrations of nocturnal leptin, growth hormone, and insulin-like growth factor-I increase before the onset of puberty in agonadal male monkeys: potential signals for the initiation of puberty.  J Clin Endocrinol Metab. 2000;  85 808-814
  • 64 Biason-Lauber A, Zachmann M, Schoenle E J. Effect of leptin on CYP17 enzymatic activities in human adrenal cells: new insight in the onset of adrenarche.  Endocrinology. 2000;  141 1446-1454
  • 65 L'Allemand D, Schmidt S, Rousson V et al.. Associations between body mass, leptin, IGF-I and circulating adrenal androgens in children with obesity and premature adrenarche.  Eur J Endocrinol. 2002;  146 537-543
  • 66 L'Allemand D, Eiholzer U, Rousson V et al.. Increased adrenal androgen levels in patients with Prader-Willi syndrome are associated with insulin, IGF-I, and leptin, but not with measures of obesity.  Horm Res. 2002;  58 215-222
  • 67 Francois I, de Zegher F. Adrenarche and fetal growth.  Pediatr Res. 1997;  41 440-442
  • 68 Ong K K, Potau N, Petry C J et al.. Avon Longitudinal Study of Parents and Children Study Team. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls.  J Clin Endocrinol Metab. 2004;  89 2647-2651
  • 69 Jaquet D, Leger J, Chevenne D, Czernichow P, Levy-Marchal C. Intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism in young women.  J Clin Endocrinol Metab. 1999;  84 3945-3949
  • 70 Boonstra V, Van Pareren Y, Hokken-Koelega A CS. Normal serum levels of DHEAS in short children born SGA.  Horm Res. 2001;  53 98-99
  • 71 Ibanez L, Potau N, Francois I, de Zegher F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth.  J Clin Endocrinol Metab. 1998;  83 3558-3562
  • 72 Biro F M, Lucky A W, Simbartl L A et al.. Pubertal maturation in girls and the relationship to anthropometric changes: pathways through puberty.  J Pediatr. 2003;  142 643-646
  • 73 Shalitin S, Phillip M. Role of obesity and leptin in the pubertal process and pubertal growth-a review.  Int J Obes Relat Metab Disord. 2003;  27 869-874
  • 74 Pratt J H, Manatunga A K, Wagner M A, Jones J J, Meaney F J. Adrenal androgen excretion during adrenarche. Relation to race and blood pressure.  Hypertension. 1990;  16 462-467
  • 75 Girgis R, Abrams S A, Castracane V D et al.. Ethnic differences in androgens, IGF-I and body fat in healthy prepubertal girls.  J Pediatr Endocrinol Metab. 2000;  13 497-503
  • 76 DiMartino-Nardi J. Pre- and postpuberal findings in premature adrenarche.  J Pediatr Endocrinol Metab. 2000;  13(Suppl 5) 1265-1269
  • 77 Vuguin P, Linder B, Rosenfeld R G, Saenger P, DiMartino-Nardi J. The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche.  J Clin Endocrinol Metab. 1999;  84 2037-2040
  • 78 Sopher A B, Thornton J C, Silfen M E et al.. Prepubertal girls with premature adrenarche have greater bone mineral content and density than controls.  J Clin Endocrinol Metab. 2001;  86 5269-5272
  • 79 Remer T, Boye K R, Hartmann M et al.. Adrenarche and bone modeling and remodeling at the proximal radius: weak androgens make stronger cortical bone in healthy children.  J Bone Miner Res. 2003;  18 1539-1546
  • 80 Wierman M E, Beardsworth D E, Crawford J D et al.. Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche.  J Clin Invest. 1986;  77 121-126
  • 81 Nadler R D, Wallis J, Roth-Meyer C, Cooper R W, Baulieu E E. Hormones and behavior of prepubertal and peripubertal chimpanzees.  Horm Behav. 1987;  21 118-131
  • 82 Herdt G, Boxer A. Children of Horizons. Beacon Press, Boston 1993
  • 83 Pattatuci A, Hamer D. Developmental and familiarity of sexual orientation in females.  Behav Genet. 1995;  25 407-420
  • 84 Dorn L D, Hitt S F, Rotenstein D. Biopsychological and cognitive differences in children with premature vs. on-time adrenarche.  Arch Pediatr Adolesc Med. 1999;  153 137-146
  • 85 Giedd J N, Castellanos F X, Rajapakse J C, Vaituzis A C, Rapoport J L. Sexual dimorphism of the developing human brain.  Prog Neuropsychopharmacol Biol Psychiatry. 1997;  21 1185-1201
  • 86 Merke D P, Fields J D, Keil M F et al.. Children with classic congenital adrenal hyperplasia have decreased amygdala volume: potential prenatal and postnatal hormonal effects.  J Clin Endocrinol Metab. 2003;  88 1760-1765
  • 87 Meaney M J, McEwen B S. Testosterone implants into the amygdala during the neonatal period masculinize the social play of juvenile female rats.  Brain Res. 1986;  398 324-328

William E RaineyPh.D. 

Division of Reproductive Endocrinology and Infertility

5323 Harry Hines Blvd

Dallas, TX 75390-9032

Email: William.Rainey@UTSouthwestern.edu

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