ABSTRACT
The primate adrenal cortex secretes high levels of 19 carbon (C19 ) steroids including dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and androstenedione. These steroids exhibit weak androgenic activity but serve as precursors for estrogens and active androgens such as testosterone. Thus, they are commonly known as adrenal androgens. Age-related changes in adrenal androgen production are well-described in humans and other primates. This article discusses the evidence for sex differences in adrenal androgen production in humans and both nonhuman primate and nonprimate animal models, which present varying degrees of sexual dimorphism in adrenal structure and function. Possible mechanisms underlying these gender differences and their relevance to human adrenocortical physiology will be discussed. Although animal and human studies have provided insight into the regulation of adrenal androgen production, the basis of the observed sex differences remains poorly understood. The putative modulation of adrenal androgen production by sex steroids merits further research, as does the possibility of gender-specific differences in adrenocortical zonation.
KEYWORDS
Adrenal androgens - gender differences - sexual dimorphism
REFERENCES
1
Culig Z, Hobisch A, Cronauer M V et al..
Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone.
Mol Endocrinol.
1993;
7
1541-1550
2
Riddick L M, Garibaldi L R, Wang M E et al..
3 alpha-androstanediol glucuronide in premature and normal pubarche.
J Clin Endocrinol Metab.
1991;
72
46-50
3
Kelnar C J, Brook C G.
A mixed longitudinal study of adrenal steroid excretion in childhood and the mechanism of adrenarche.
Clin Endocrinol (Oxf).
1983;
19
117-129
4
Gell J S, Carr B R, Sasano H et al..
Adrenarche results from development of a 3beta-hydroxysteroid dehydrogenase-deficient adrenal reticularis.
J Clin Endocrinol Metab.
1998;
83
3695-3701
5
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
6
Cutler Jr G B, Loriaux D L.
Andrenarche and its relationship to the onset of puberty.
Fed Proc.
1980;
39
2384-2390
7
Miller W L.
The molecular basis of premature adrenarche: an hypothesis.
Acta Paediatr Suppl.
1999;
88
60-66
8
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
9
Cutler Jr G B, Glenn M, Bush M et al..
Adrenarche: a survey of rodents, domestic animals, and primates.
Endocrinology.
1978;
103
2112-2118
10
Collins D C, Nadler R D, Preedy J RK.
Adrenarche in the great apes.
Am J Primato.
1981;
1
344
11
Stoinski T S, Czekala N, Lukas K E, Maple T L.
Urinary androgen and corticoid levels in captive, male Western lowland gorillas (Gorilla g. gorilla): age- and social group-related differences.
Am J Primatol.
2002;
56
73-87
12
Baulieu E E.
Dehydroepiandrosterone (DHEA): a fountain of youth?.
J Clin Endocrinol Metab.
1996;
81
3147-3151
13
Perkins L M, Payne A H.
Quantification of P450scc, P450(17) alpha, and iron sulfur protein reductase in Leydig cells and adrenals of inbred strains of mice.
Endocrinology.
1988;
123
2675-2682
14
Le Goascogne C, Sananes N, Gouezou M et al..
Immunoreactive cytochrome P-450(17 alpha) in rat and guinea-pig gonads, adrenal glands and brain.
J Reprod Fertil.
1991;
93
609-622
15
Tremblay Y, Belanger A, Fleury A et al..
Studies of the guinea pig adrenal cytochrome P450c17 cDNA.
Endocr Res.
1995;
21
495-507
16
van Weerden W M, Bierings H G, van Steenbrugge G J, de Jong F H, Schroder F H.
Adrenal glands of mouse and rat do not synthesize androgens.
Life Sci.
1992;
50
857-861
17
Keeney D S, Jenkins C M, Waterman M R.
Developmentally regulated expression of adrenal 17 alpha-hydroxylase cytochrome P450 in the mouse embryo.
Endocrinology.
1995;
136
4872-4879
18
Heikkila M, Peltoketo H, Leppaluoto J et al..
Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production.
Endocrinology.
2002;
143
4358-4365
19
Pawlus M.
Genetic differences in mouse adrenocortical structure.
Folia Histochem Cytochem (Krakow).
1983;
21
239-251
20
Tanaka S, Matsuzawa A.
Comparison of adrenocortical zonation in C57BL/6J and DDD mice.
Exp Anim.
1995;
44
285-291
21
Beuschlein F, Keegan C E, Bavers D L et al..
SF-1, DAX-1, and acd: molecular determinants of adrenocortical growth and steroidogenesis.
Endocr Res.
2002;
28
597-607
22
Perry J E, Stalvey J R.
Gonadal steroids modulate adrenal fasciculata 3 beta-hydroxysteroid dehydrogenase-isomerase activity in mice.
Biol Reprod.
1992;
46
73-82
23
Stalvey J R.
Inhibition of 3beta-hydroxysteroid dehydrogenase-isomerase in mouse adrenal cells: a direct effect of testosterone.
Steroids.
2002;
67
721-731
24
Mukai T, Kusaka M, Kawabe K et al..
Sexually dimorphic expression of Dax-1 in the adrenal cortex.
Genes Cells.
2002;
7
717-729
25
Vinson G P, Whitehouse B J, Goddard C.
The effect of sex and strain of rats on the in vitro response of adrenocortical tissue of ACTH stimulation.
J Steroid Biochem.
1978;
9
553-560
26
Johnson D C.
Steroid 17 alpha-hydroxylase of the rat adrenal.
J Steroid Biochem.
1979;
10
397-400
27
Pelletier G, Li S, Luu-The V et al..
Immunoelectron microscopic localization of three key steroidogenic enzymes (cytochrome P450(scc), 3 beta-hydroxysteroid dehydrogenase and cytochrome P450(c17)) in rat adrenal cortex and gonads.
J Endocrinol.
2001;
171
373-383
28
Rogler L E, Pintar J E.
Expression of the P450 side-chain cleavage and adrenodoxin genes begins during early stages of adrenal cortex development.
Mol Endocrinol.
1993;
7
453-461
29
Calandra R S, Purvis K, Naess O et al..
Androgen receptors in the rat adrenal gland.
J Steroid Biochem.
1978;
9
1009-1015
30
Bentvelsen F M, McPhaul M J, Wilson C M, Wilson J D, George F W.
Regulation of immunoreactive androgen receptor in the adrenal gland of the adult rat.
Endocrinology.
1996;
137
2659-2663
31
Brush F R, Isaacson M D, Pellegrino L J, Rykaszewski I M, Shain C N.
Characteristics of the pituitary-adrenal system in the Syracuse high- and low-avoidance strains of rats (Rattus norvegicus).
Behav Genet.
1991;
21
35-48
32
Wiesenfeld P, Michaelis O E.
Gender differences in adrenal cortex steroid production in SHR/N-corpulent rats.
Proc Soc Exp Biol Med.
1994;
207
254-259
33
Tanaka S, Nozaki M, Fujioka T, Matsuzawa A.
Adrenocortical zonation of inbred wild-coloured mastomys, Praomys coucha: a new border zone in the cortex of females.
Lab Anim.
1990;
24
5-13
34
Tanaka S, Nozaki-Ukai M, Kitoh J, Matsuzawa A.
Genetic regulation of border zone formation in female mastomys (Praomys coucha) adrenal cortex.
J Hered.
1996;
87
70-74
35
Tanaka S, Nozaki M, Fujioka T, Matsuzawa A.
Adrenocortical zonation of inbred wild-coloured mastomys, Praomys coucha: a new border zone in the cortex of females.
Lab Anim.
1990;
24
5-13
36
Cloutier M, Fleury A, Courtemanche J et al..
Characterization of the adrenal cytochrome P450C17 in the hamster, a small animal model for the study of adrenal dehydroepiandrosterone biosynthesis.
DNA Cell Biol.
1997;
16
357-368
37
Pieper D R, Lobocki C A.
Characterization of serum dehydroepiandrosterone secretion in golden hamsters.
Proc Soc Exp Biol Med.
2000;
224
278-284
38
Belanger B, Caron S, Boudou P, Fiet J, Belanger A.
Adrenal steroidogenesis in the guinea pig: effects of androgens.
Steroids.
1992;
57
76-81
39
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
E694-699
40
Tagliaferro A R, Ronan A M.
Physiological levels and action of dehydroepiandrosterone in Yucatan miniature swine.
Am J Physiol Regul Integr Comp Physiol.
2001;
281
R1-R9
41
McNulty W P, Novy M J, Walsh S W.
Fetal and postnatal development of the adrenal glands in Macaca mulatta.
Biol Reprod.
1981;
25
1079-1089
42
Levine J, Wolfe L G, Schiebinger R J, Loriaux D L, Cutler Jr G B.
Rapid regression of fetal adrenal zone and absence of adrenal reticular zone in the marmoset.
Endocrinology.
1982;
111
1797-1802
43
Ducsay C A, Hess D L, McClellan M C, Novy M J.
Endocrine and morphological maturation of the fetal and neonatal adrenal cortex in baboons.
J Clin Endocrinol Metab.
1991;
73
385-395
44
Mapes S, Corbin C J, Tarantal A, Conley A.
The primate adrenal zona reticularis is defined by expression of cytochrome b5, 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17) and NADPH-cytochrome P450 reductase (reductase) but not 3beta-hydroxysteroid dehydrogenase/delta5-4 isomerase (3beta-HSD).
J Clin Endocrinol Metab.
1999;
84
3382-3385
45
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.
Endocr Res.
2000;
26
517-522
46
Mesiano S, Coulter C L, Jaffe R B.
Localization of cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17 alpha-hydroxylase/17, 20-lyase, and 3 beta-hydroxysteroid dehydrogenase isomerase steroidogenic enzymes in human and rhesus monkey fetal adrenal glands: reappraisal of functional zonation.
J Clin Endocrinol Metab.
1993;
77
1184-1189
47
Serón-Ferré M, Taylor N F, Rotten D, Koritnik D R, Jaffe R B.
Changes in fetal rhesus monkey plasma dehydroepiandrosterone sulfate: relationship to gestational age, adrenal weight and preterm delivery.
J Clin Endocrinol Metab.
1983;
57
1173-1178
48
Mapes S, Tarantal A F, Parker C R et al..
Adrenocortical cytochrome b5 expression during fetal development of the rhesus macaque.
Endocrinology.
2002;
143
1451-1458
49
Kemnitz J W, Roecker E B, Haffa A L et al..
Serum dehydroepiandrosterone sulfate concentrations across the life span of laboratory-housed rhesus monkeys.
J Med Primatol.
2000;
29
330-337
50
Hirst J J, West N B, Brenner R M, Novy M J.
Steroid hormone receptors in the adrenal glands of fetal and adult rhesus monkeys.
J Clin Endocrinol Metab.
1992;
75
308-314
51
Goncharova N D, Lapin B A.
Effects of aging on hypothalamic-pituitary-adrenal system function in non-human primates.
Mech Ageing Dev.
2002;
123
1191-1201
52
Castracane V D, Cutler Jr G B, Loriaux D L.
Pubertal endocrinology of the baboon: adrenarche.
Am J Physiol.
1981;
241
E305-E309
53
Giussani D A, Farber D M, Jenkins S L et al..
Opposing effects of androgen and estrogen on pituitary-adrenal function in nonpregnant primates.
Biol Reprod.
2000;
62
1445-1451
54
Wu S S, Nathanielsz P W, McDonald T J.
Immunocytochemical distribution of androgen receptors in the hypothalamus and pituitary of the fetal baboon in late gestation.
Brain Res Dev Brain Res.
1995;
84
278-281
55
Mann D R, Castracane V D, McLaughlin F, Gould K G, Collins D C.
Developmental patterns of serum luteinizing hormone, gonadal and adrenal steroids in the sooty mangabey (Cercocebus atys).
Biol Reprod.
1983;
28
279-284
56
Pattison J C, Mapes S M, Pryce C R, Conley A J, Bird I M.
Marmosets express a fetal zone at birth but no ZR in adulthood.
Endocr Res.
2002;
28
675
57
Pattison J C, Corbin J, Saltzman W et al..
Gender differences in cytochrome b5 expression in the common marmoset adrenal gland.
J Soc Gynecol Investig.
2003;
10
384A
58
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
59
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
60
Satta Y, Klein J, Takahata N.
DNA archives and our nearest relative: the trichotomy problem revisited.
Mol Phylogenet Evol.
2000;
14
259-275
61
Chen F C, Li W H.
Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees.
Am J Hum Genet.
2001;
68
444-456
62
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
63
Copeland K C, Eichberg J W, Parker Jr C R, Bartke A.
Puberty in the chimpanzee: somatomedin-C and its relationship to somatic growth and steroid hormone concentrations.
J Clin Endocrinol Metab.
1985;
60
1154-1160
64
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
65
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
66
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
67
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
68
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
69
Ilondo M M, Vanderschueren-Lodeweyckx M, Vlietinck R et al..
Plasma androgens in children and adolescents. Part II. A longitudinal study in patients with hypopituitarism.
Horm Res.
1982;
16
78-95
70
Odell W D, Parker L N.
Control of adrenal androgen production.
Endocr Res.
1984;
10
617-630
71
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
72
Parker Jr C R, Stankovic A M, Goland R S.
Corticotropin-releasing hormone stimulates steroidogenesis in cultured human adrenal cells.
Mol Cell Endocrinol.
1999;
155
19-25
73
Rehman K S, Sirianni R, Carr B R, Rainey W E.
The role of sex steroids in adrenal function: differences in androgen and estrogen receptor expression in adrenal tissue.
J Soc Gynecol Investig.
2003;
10
383A
74
Hyatt P J, Bhatt K, Tait J F.
Steroid biosynthesis by zona fasciculata and zona reticularis cells purified from the mammalian adrenal cortex.
J Steroid Biochem.
1983;
19
953-959
75
Donaldson A, Nicolini U, Symes E K, Rodeck C H, Tannirandorn Y.
Changes in concentrations of cortisol, dehydroepiandrosterone sulphate and progesterone in fetal and maternal serum during pregnancy.
Clin Endocrinol (Oxf).
1991;
35
447-451
76
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
77
Challis J RG, Matthews S G, Gibb W, Lye S J.
Endocrine and paracrine regulation of birth at term and preterm.
Endocr Rev.
2000;
21
514-550
78
Yuen B H, Mincey E K.
Human chorionic gonadotropin, prolactin, estriol, and dehydroepiandrosterone sulfate concentrations in cord blood of premature and term newborn infants: relationship to the sex of the neonate.
Am J Obstet Gynecol.
1987;
156
396-400
79
de Peretti E, Forest M G.
Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in human: the use of a sensitive radioimmunoassay.
J Clin Endocrinol Metab.
1976;
43
982-991
80
Simmons D, France J T, Keelan J A, Song L, Knox B S.
Sex differences in umbilical cord serum levels of inhibin, testosterone, oestradiol, dehydroepiandrosterone sulphate, and sex hormone-binding globulin in human term neonates.
Biol Neonate.
1994;
65
287-294
81
Rabinovici J, Jaffe R B.
Development and regulation of growth and differentiated function in human and subhuman primate fetal gonads.
Endocr Rev.
1990;
11
532-557
82
Dawood M Y, Saxena B B.
Testosterone and dihydrotestosterone in maternal and cord blood and in amniotic fluid.
Am J Obstet Gynecol.
1977;
129
37-42
83
Potau N, Ibanez L, Sentis M, Carrascosa A.
Sexual dimorphism in the maturation of the pituitary-gonadal axis, assessed by GnRH agonist challenge.
Eur J Endocrinol.
1999;
141
27-34
84
Wabitsch M, Blum W F, Muche R et al..
Contribution of androgens to the gender difference in leptin production in obese children and adolescents.
J Clin Invest.
1997;
100
808-813
85
Weise M, Eisenhofer G, Merke D P.
Pubertal and gender-related changes in the sympathoadrenal system in healthy children.
J Clin Endocrinol Metab.
2002;
87
5038-5043
86
Young D G, Skibinski G, Mason J I, James K.
The influence of age and gender on serum dehydroepiandrosterone sulphate (DHEA-S), IL-6, IL-6 soluble receptor (IL-6 sR) and transforming growth factor beta 1 (TGF-beta1) levels in normal healthy blood donors.
Clin Exp Immunol.
1999;
117
476-481
87
Šulcová J, Hill M, Hampl R, Starka L.
Age and sex related differences in serum levels of unconjugated dehydroepiandrosterone and its sulphate in normal subjects.
J Endocrinol.
1997;
154
57-62
88
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
89
Mesiano S, Jaffe R B.
Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production.
J Clin Endocrinol Metab.
1993;
77
754-758
90
Gell J S, Oh J, Rainey W E, Carr B R.
Effect of estradiol on DHEAS production in the human adrenocortical cell line, H295R.
J Soc Gynecol Investig.
1998;
5
144-148
91
Hines G A, Smith E R, Azziz R.
Influence of insulin and testosterone on adrenocortical steroidogenesis in vitro: preliminary studies.
Fertil Steril.
2001;
76
730-735
92
Carmina E, Gonzalez F, Vidali A et al..
The contributions of oestrogen and growth factors to increased adrenal androgen secretion in polycystic ovary syndrome.
Hum Reprod.
1999;
14
307-311
93
Rosenfield R L, Lawrence A M, Liao S, Landau R L.
Androgens and androgen responsiveness in the feminizing testis syndrome.
Comparison of complete and “incomplete” forms. J Clin Endocrinol Metab.
1971;
32
625-632
94
Forti G, Giusti G, Borghi A et al..
Klinefelter's syndrome: a study of its hormonal plasma pattern.
J Endocrinol Invest.
1978;
1
149-154
95
Lobo R A, Goebelsmann U, Brenner P F, Mishell Jr D R.
The effects of estrogen on adrenal androgens in oophorectomized women.
Am J Obstet Gynecol.
1982;
142
471-478
96
De Leo V, la Marca A, Talluri B, D'Antona D, Morgante G.
Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal women.
Eur J Endocrinol.
1998;
138
430-435
97
Secreto G, Recchione C, Zambetti M, Fariselli G, Ballerini P.
Hormonal changes induced by the pure antiandrogen flutamide in postmenopausal women with advanced breast cancer.
Eur J Cancer Clin Oncol.
1988;
24
867-872
98
Belanger A, Dupont A, Labrie F.
Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer.
J Clin Endocrinol Metab.
1984;
59
422-426
99
De Leo V, la Marca A, Lanzetta D et al..
Effects of flutamide on pituitary and adrenal responsiveness to corticotrophin releasing factor (CRF).
Clin Endocrinol (Oxf).
1998;
49
85-89
100
Müderris I I, Bayram F, Guven M.
A prospective, randomized trial comparing flutamide (250 mg/d) and finasteride (5 mg/d) in the treatment of hirsutism.
Fertil Steril.
2000;
73
984-987
Khurram S RehmanM.D.
Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center
5323 Harry Hines Blvd
Rm. J6.114, Dallas, TX 75390-9032
Email: khurram.rehman@utsouthwestern.edu