ENDOCRINE REGULATIONS, Vol. 35, 95100, 2001 95 ADRENAL ANDROGENS REGULATION AND ADRENOPAUSE SALVATORE ALESCI 1, CHRISTIAN A. KOCH 1, STEFAN R. BORNSTEIN1, KAREL PACAK1,2 1Pediatric & Reproductive Endocrinology Branch , National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD ( USA ); 2Institute of Endocrinology, Prague, Czech Republic E-mail : [email protected] Adrenal androgens (AA) are mainly produced by the human adrenal cortex. ACTH is the major regulator of their secretion. However, other factors, such as gonadal sex steroids, insulin, growth hormone, prolactin, hypothalamic peptides and growth factors have been involved in AA regula- tion. More recently, it has become well accepted that, besides systemic factors, AA secretion is under the control of the sympathoadrenal system and immunoadrenal system. Here we review the extraadrenal and intraadrenal mechanisms of AA regulation and how they may relate to endo- crinoimmunosenescence. Key words : DHEA Adrenal androgens Adrenopause Aging ACTH Minireview Human adrenals produce large amounts of andro- that they may have both androgenic and estrogenic gens, especially dehydroepiandrosterone (DHEA) effect. ADION and T are responsible for 85-90% of and dehydroepiandrosterone sulfate (DHEAS), the total androgenic activity of the adrenal gland, which are the most abundant circulating hormones while DHEA and ADIOL account for the remaining in the human body (ADAMS 1985). Adrenal andro- 10%, being their androgen action mainly dependent gens (AA) are mainly synthesized in the inner zona on conversion to T and 5α-dihydrotestosterone in reticularis (ZR) of the adrenal cortex from the pre- peripheral tissues. ADION is the most important pre- cursor pregnenolone, derived from side-chain cleav- cursor of estrone, the major circulating estrogen in age of cholesterol by cytochrome P450scc enzyme postmenopausal women, while ADIOL can act as (CYPscc). Cytochrome P450-17α (CYP17), a 17α- a classic estrogen both in vitro and in vivo (ADAMS hydroxylase with 17,20-lyase activity converts the 1985). C-21 steroid pregnenolone to the C-19 steroid DHEA, AA production follows a characteristic age-relat- while a hydroxysteroid sulfotransferase (DHEAST) ed pattern. The human fetal adrenal gland undergoes converts DHEA to DHEAS. Alternatively, the ∆5 extensive growth in utero. At the end of gestation, it androgen DHEA can be converted to the ∆4 andro- weighs approximately the same as the adult adrenal gen androstenedione (ADION) by the microsomal because of the presence of a large fetal zone. non-P450 enzyme 3β-hydroxysteroid dehydrogena- A dramatic involution of this zone occurs by un- se (3βHSD) or to androstenediol (ADIOL) by the known mechanism in the first month after birth and 17β-hydroxysteroid oxidoreductase (17βHSOX), continues during the first years of life, being paral- which can also convert ADION to testosterone (T) leled by a sharp decrease in DHEAS, which was the (PARKER 1991). predominant circulating steroid at birth, while corti- The exact biological function of AA is still sol levels remain relatively constant (DE PERETTI and a matter of discussion. However, it is well known FOREST 1978). During the peripubertal period, the 96 DHEA AND ADRENOPAUSE Table 1 Gonadal androgens, for example, have been shown Physiological and pathological states characterized by to inhibit 11β and 21α hydroxylases a divergence of cortisol and (FUJIEDA et al. 1982), while estrogens have been adrenal androgen secretion. reported to stimulate DHEA and DHEAS in vitro PHYSIOLOGICAL. PATHOLOGICAL (GELL et al. 1998) and in vivo (SOBRINHO et al. 1971). Fetal stage Idiopathic hirsutism In addition, DHEAS levels are higher in males vs Obesity, fasting and anorexia nervosa females and sex hormone therapy may reverse this Acute stress from illness or trauma difference (POLDERMAN et al. 1994) Adrenarche Secondary and Tertiary Adrenal insufficiency Insulin at physiological concentrations increases Cushings disease mRNA levels of 17α-hydroxylase and type II 3βHSD Primary cortisol resistance in the absence of cAMP or ACTH in primary cul- Puberty Congenital adrenal hyperplasia tures of human adrenocortical cells (KRISTIANSEN et Ectopic ACTH Syndrome al. 1997), while insulin growth factor I (IGF-I) stim- Partial hypopituitarism Aging End-stage renal disease ulates androgen biosynthesis through the interaction with IGF-I receptor and IGF-I binding proteins in human adrenal primary cultures (FOTTNER et al. 1998). Growth hormone (GH) increases DHEAS levels adrenal gland undergoes a process of maturation, in human fetal adrenals (BROWN et al. 1978), but on with progressive broadening of the inner cortical area the other hand, AA are suppressed in patients with and creation of the zona reticularis. This is accom- GH deficiency (COHEN et al. 1981). panied by an elevation in AA concentration called Prolactin (PRL) stimulates steroidogenesis in guin- adrenarche which contributes to the development ea-pig (O CONNELL et al. 1994) and human (GLASOW of pubic and axillary hair in both sexes. Again, de- et al. 1996) adrenals in vitro. However, no correla- spite this increase in AA secretion, concentration, tions between PRL and AA levels through different excretion and average production of cortisol remain stages of life have been found (PARKER et al. 1978; costant (PARKER et al. 1978). Secretion of GnRH at HAMMOND et al. 1979). puberty activates the pituitary-gonadal axis causing Among the pituitary peptides, β-endorphin, β-li- a large increase in concentrations of testosterone and potropin and other peptides derived from pro-opi- estradiol in boys and girls respectively. During this omelanocortin (POMC) have been linked to AA reg- time, we also observe an increase in DHEA, DH- ulation. B-endorphin and β-lipotropin levels rise with EAS and ADION, which continues through the third adrenarche (GENAZZANI et al. 1983) and are high in decade of life (ADAMS 1985; PARKER 1991). Aging in polycystic ovary syndrome (ALEEM and MCINTOSH healthy people is accompanied by only little chang- 1984). Another POMC-derived peptide, the so-called es in serum cortisol or aldosterone. In sharp contrast, joining peptide has been shown to stimulate AA a mark decline in both AA secretion and excretion is secretion in vitro (PARKER et al. 1989; CLARKE et al. observed in the elderly and is commonly named 1996; ORSO et al. 1996). However, such findings have adrenopause. been contested (MELLON et al. 1991; PENHOAT et al. 1991; ROBINSON et al., 1991). Extra- and intra-adrenal regulation of adrenal More recently the corticotropin-releasing hormone androgens (CRH) has been shown to stimulate DHEA secretion from human fetal adrenals (SMITH et al. 1998) and in The mechanisms underlying AA control are still young men (IBANEZ et al. 1999). Recent evidence also object of animate debate. Without any doubt, adreno- suggests that the CRH-induced increase of adrenal corticotropin (ACTH) plays an important role in stim- steroidogenesis can be blocked by CRH type-I recep- ulating AA production. However, several instances tor antagonists, which may suggest a role for this re- of dissociation between cortisol and AA secretion ceptor in AA regulation (WILLENBERG et al. 2000). (Tab 1) suggest that besides ACTH, other factors are Some growth factors have been related to AA reg- involved in AA regulation (CUTLER et al. 1979). ulation. Epidermal growth factor (EGF) and fibro- DHEA AND ADRENOPAUSE 97 blast growth factor (FGF) stimulate growth of bo- (HEYM et al. 1994), stimulates both the release of vine adrenocortical cells in vitro (HORNSBY 1985), androstenedione and DHEA (BORNSTEIN et al. 1996; while transforming growth factor β (TGF-β) reduc- HAIDAN et al. 1998). es DHEAS by increasing mRNA accumulation of Similarly, direct cellular contacts between lym- 3βHSD and decreasing those of CYP17 (LEBRETHON phocytes and ZR cells through filopodia and gap et al. 1994; STANKOVIC et al. 1994). junctions have been recently described (WOLKERS- The existence of a specific adrenal androgens DORFER et al. 1999). Moreover, activated macroph- stimulating hormone (AASH) has been postulated ages, producing IL-1, IL-6 and TNF α have been twenty years ago. However, despite claims for the demonstrated in ZR, (BORNSTEIN and CHROUSOS 1999). isolation of such a tropic hormone (PARKER et al. This intraadrenal immune-system may play a role in 1983), the evidence for this is not so striking and the the regulation of AA secretion. IL-6 stimulates the need for the existence of a separate AASH other than release of DHEA in human adrenal primary cell cul- ACTH has been often disputed. NEVILLE and OHARE ture (PAETH et al. 1997) while TNF α has been shown (1982), for example, emphasize the lack of relevant to blunt the effects of ACTH on DHEA sulfotrans- pathophysiological syndromes AASH-related, such ferase mRNA and, with less extent, on CYP17 as AASH-secreting pituitary tumors. ANDERSON mRNA in human fetal adrenal cells (LANGLOIS et al. (1980) states that the AASH does not exist and 1998 ; PARKER et al. 1998). adrenarche is related to morphological and functional change in the ZR. According to this author, the slow Adrenal androgens and adrenopause: flush-out of reticularis blood vessels after each pulse a hypothesis of ACTH would expose the inner-zone cells to the highest cortisol levels (the cortisol they produce As mentioned earlier in this paper, AA secretion themselves plus that secreted from all the cells up- in humans increases dramatically just before puber- stream) for the longest time. Progressively, ZR cells ty, during the so-called adrenarche, reaching peak would start responding to these high cortisol levels levels in the third decade of life (ADAMS 1985; PARK- by undergoing modifications in enzymatic activities, ER 1991). Then, AA levels start falling, with values with a decrease in 3βHSD and an increase in 17,20- of 20% (men) to 30% (women) of the peak by the lyase, which would explain the increased production age of 70 to 80 and the greatest decline occurring by of AA during adrenarche. (ANDERSON 1980). Differ- the ages of 50-60, the so-called adrenopause (KRO- ently, RICH et al.