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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4431-4435
Copyright © 1999 by The Endocrine Society

Special Articles

Adrenal Hyperandrogenism in Children

Lucia Ghizzoni, George Mastorakos and Alessandra Vottero

Department of Pediatrics (L.G., A.V.), University of Parma, 43100 Parma, Italy; and Endocrine Unit (G.M.), Evgenidion Hospital, Athens University, 11528 Athens, Greece

Address correspondence and requests for reprints to: Lucia Ghizzoni, M.D., Clinica Pediatrica, Universita’ degli Studi di Parma, Via Gramsci 14, 43100 Parma, Italy. E-mail: lughizzo{at}unipr.it


   Introduction
Top
 Introduction
Adrenal Androgen Physiology
 Etiology of Adrenal Androgen...
 Conclusion
 References
 
HYPERANDROGENISM of a mild-to-moderate degree is probably the most common abnormality in normoestrogenic menstrual disturbances. Androgen excess arises from abnormal ovarian or adrenal sources. The adrenal androgens, normally secreted by the fetal adrenal zone or the zona reticularis, are steroid hormones with weak androgen activity. Although adrenal androgens do not seem to play a major role in the fully androgenized adult men, they seem to play a role in the adult woman and in both sexes before puberty. Girls, women, as well as prepubertal boys may be negatively affected by adrenal androgen hypersecretion in contrast to adult men.

In this review, we examine the roles and effects of adrenal androgens and analyze the clinical significance of their hypersecretion during childhood.


   Adrenal Androgen Physiology
Top
 Introduction
 Adrenal Androgen Physiology
Etiology of Adrenal Androgen...
 Conclusion
 References
 
The adrenal cortex is divided into three histological and functional zones: the outer, aldosterone-secreting zona glomerulosa; the intermediate, cortisol-secreting, zona fasciculata; and the inner, androgen-secreting, zona reticularis. In the fetus, the adrenal cortex consists of the two adult adrenal zonae glomerulosa and fasciculata and an inner large fetal adrenal zone, which virtually disappears within weeks after birth. Remaining cell foci from the fetal adrenal zone presumably give rise to the adrenal zona reticularis starting at the age of 4–5 yr in both sexes. This zone continues to grow until young adulthood (20–25 yr), remains at a plateau for 5–10 yr, and regresses gradually after the age of 35 yr.

The major androgens secreted by the adrenals are dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione ({Delta}4-A). Production of testosterone (T) by these glands is minimal (1). DHEA and DHEA-S are mainly the products of zona reticularis, {Delta}4-A and testosterone T are secreted by both zona reticularis and zona fasciculata (2, 3). Adrenal androgens are secreted in small amounts during infancy and early childhood, and their secretion gradually increases with age, paralleling the growth of the zona reticularis (4). The mechanism(s) by which this zone develops with age and the regulation of its secretion are not fully known. During this process, plasma concentrations of the adrenal androgens increase, whereas those of cortisol remain stable, suggesting that factors other than corticotropin are involved. These may include the elusive androgen-stimulating factor (AASF) (Fig. 1Go), the existence of which has been repeatedly questioned (5, 6). A programmed shift in production of intradrenal regulatory factors associated with differentiation of adrenal cells and changes in steroid biosynthesis might also take place independently of circulating factors.



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  		Figure 1. Schematic representation of the causes of adrenal hyperandrogenism in children.

 
Adrenal androgens are secreted by the adrenal glands in response to their tropic hormone ACTH (2) (Fig. 1Go). This is a 39-amino acid peptide synthesized and secreted by the anterior pituitary under the regulatory control of CRH and arginine-vasopressin (7, 8). Under ACTH regulation, adrenal androgens are secreted synchronously with cortisol, in both the secretory episodes and the circadian pattern (9, 10). Corticotropin-stimulated cortisol exerts major feedback inhibitory influences at the level of both the hypothalamus and the anterior pituitary by suppressing CRH, arginine-vasopressin, and ACTH synthesis and secretion. Furthermore, the hypothalamic-pituitary-adrenal (HPA) axis exerts both negative and positive influences on GH secretion (11), as well as a primarily negative influence on the secretion of TSH (12). Under physiological conditions, the HPA axis has also a prevailing inhibitory effect on leptin secretion (Ghizzoni, L., personal communication).

Steroid precursors and the adrenal androgens themselves may be respectively converted to androgens or more potent androgens in peripheral tissues, such as hair follicles, sebaceous glands, prostate, and external genitalia (13). Major conversions are those of {Delta}4-A to T and T to dihydrotestosterone by the enzymes 17-ketosteroid reductase and 5{alpha}-reductase, respectively. Active uptake of androgens and in situ estrogen synthesis occur in peripheral adipose tissue, where the aromatization of {Delta}4-A and T to estrone and estradiol, respectively, occurs. The adrenal androgens and their metabolites are inactivated at various tissues, including the liver and kidney (14).


   Etiology of Adrenal Androgen Hypersecretion (Table 1Go)
Top
 Introduction
 Adrenal Androgen Physiology
 Etiology of Adrenal Androgen...
Conclusion
 References
 
Primary adrenal causes

Premature pubarche.Premature pubarche refers to the appearance of pubic hair before age 8 yr in girls and 9 yr in boys, without other signs of puberty or virilization (15). Axillary hair, apocrine odor, and acne may or may not be present. Growth velocity may be increased, and slightly advanced bone maturation is often present and is usually well correlated with the height age. The transient acceleration of growth and of bone maturation have no negative effects on the onset and progression of puberty and on final height (16). The precise etiology of premature pubarche is not known. Generally, it has been attributed to the early maturation of the zona reticularis, which leads to an increase of adrenal androgens to levels normally seen in early puberty (17, 18). It has also been proposed that an increase in androgen biosynthesis might be due to the preferential hyperphosporylation of the enzyme P450c17 due to an autosomal dominant activating mutation of the kinase responsible for the serine/threonine phosphorylation of the enzyme (19). Because serine phosphorylation of P450c17, the key regulatory enzyme controlling androgen biosynthesis, has been shown in vitro to increase its activity (19), it is possible that the same mechanism can cause in vivo increased androgen production. Adrenal steroid, cortisol, ACTH, and ß-endorphin-immunoreactivity responses to human CRH stimulation test are similar in normal children and children with premature pubarche, suggesting that CRH does not seem to play a role in premature pubarche (20).


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  		Table 1. Etiology of adrenal androgen hypersecretion in children

 
The diagnosis is based on the exclusion of true precocious puberty and the nonclassic forms of congenital adrenal hyperplasia. The incidence of defective steroidogenesis in children with premature pubarche is extremely variable, ranging from 0% in some reports (21) to 40% in others (22), probably due to the varying ethnic background of the populations studied. Recently (23), a high incidence of molecular defects of the CYP21 gene was reported in Greek children with premature pubarche, the majority of whom were heterozygotes for 9 different molecular defects. Whether this finding has any general clinical relevance, only long-term prospective studies will be able to establish it. Since idiopathic precocious puberty is generally characterized by pubertal progression of the hypothalamic-pituitary-gonadal axis,it can usually be clinically distinguished from premature pubarche. The plasma concentrations of DHEA, DHEA-S, and {Delta}4-A, as well as the levels of the 17-ketosteroids and their urinary metabolites, are increased for age and similar to those normally found in pubertal children with Tanner stage II of pubertal development (4, 24). ACTH stimulation test rules out nonclassic congenital adrenal hyperplasia, but not the carrier state (4). Gonadotropin levels are in the prepubertal normal range both at basal state and after stimulation with gonadotropin-releasing hormone.

Once precocious puberty and nonclassic congenital adrenal hyperplasia are excluded, no treatment is needed. However, a long-term follow-up of these patients is warranted. Recent data, in fact, indicate that girls with premature pubarche may not have a benign outcome. Postpubertal girls diagnosed with premature pubarche during childhood have an increased frequency of functional ovarian hyperandrogenism (25). Furthermore, hyperinsulinemia is a common feature in adolescent patients with premature pubarche and functional ovarian hyperandrogenism and is directly related to the degree of androgen excess (26, 27, 28). Although the mechanisms interlinking the triad of hyperinsulinemia, premature pubarche, and ovarian hyperandrogenism remain enigmatic, this frequent concurrence may result, at least in part, from a common genetic or early origin, as the result of in utero growth retardation (29).

In polycystic ovary syndrome, the insulin resistance has been shown to be the result of a postbinding defect in insulin receptor signal transduction that seems to be due to a constitutively increased receptor serine phosphorylation that inhibits the receptor tyrosine kinase activity (30). Serine phosphorylation of P450c17, the key regulatory enzyme controlling androgen biosynthesis has also been shown in vitro to increase its activity (19). This could result in increased androgen production. Thus, the same factor could lead to insulin resistance in adulthood and hyperandrogenism by serine-phosphorylation-mediated changes in different enzymatic activities.

Adrenal tumors.Adrenal tumors are divided into benign and malignant groups (adenomas and carcinomas, respectively) and can be hormone secreting or nonsecreting (31, 32, 33). The exact incidence of these tumors in children is not known; they are relatively rare, but most often malignant. The age of appearance is usually during the 1st decade of life (34). Females are more frequently affected than males (2.5:1) (35). Primary adrenal tumors may autonomously hypersecrete androgens and/or other hormones (31). Generally, the supraphysiologic amount of androgens secreted by these tumors is characterized by extremely elevated circulating DHEA and DHEA-S levels. Other androgens, such as {Delta}4-A and T, may also be elevated by either direct secretion or peripheral conversion of DHEA and DHEA-S.

The clinical manifestations of patients with androgen-secreting adrenal tumors depend on the nature of the hormones secreted; most frequently, however, children with adrenocortical cancers present with virilization in females and early puberty in males (32). Glucocorticoid overproduction occurs occasionally in conjunction with virilizing tumors, but patients may not present with Cushingoid features. The onset of the disease is sudden, and hormonal symptoms are rapidly progressive. Because of the anatomic location of the adrenal tumors, as well as the nonsecreting nature of some of them, adrenal adenomas or carcinomas may remain undiagnosed for a considerable period of time.

Benign virilizing adrenocortical adenomas are usually small (diameter <5 cm) and not visible on ultrasound, but are visible on computed tomographic or magnetic resonance imaging (MRI) scans. These tumors do not show enhancement at the T2 relaxation time of MRI. Plasma concentrations of adrenal androgens and/or T are elevated and usually not suppressed by dexamethasone.

Malignant virilizing adrenocortical carcinomas are generally larger than 5 cm in diameter and have already invaded the capsule of the gland or neighboring tissues by the time they are discovered. They can produce several steroid intermediates, adrenal androgens, and/or T, as well as compounds with glucocorticoid and mineralocorticoid activity (31). These steroids are nonsuppressible by dexamethasone. These tumors are frequently palpable or visible on ultrasound and, unlike benign adenomas, their MRI shows enhancement at the T2 relaxation time.

Potential mechanisms that could be particularly important in adrenocortical tumorigenesis include abnormalities in recently described factors specific to the adrenal cortex. These include the steroidogenic acute regulatory protein (36), which enhances the mitochondrial conversion of cholesterol into pregnenolone by the cholesterol side-chain cleavage enzyme, steroidogenic factor I (37), an orphan nuclear receptor that is a key regulator of the steroid hydroxylase in adrenocortical cells, and a new member of the nuclear receptor superfamily called DAX-I (38). The product of the latter acts as a dominant negative regulator of transcription mediated by the retinoic acid receptor. Recently, steroidogenic acute regulatory protein mRNA has been found expressed at high levels in normal human adrenals and adrenocortical tumors (36). On the other hand, whether abnormalities in the gene encoding for steroidogenic factor I or in the DAX-1 gene might be associated with human adrenocortical tumorigenesis remains unknown.

Complete surgical excision with replacement steroid therapy provides the best therapeutic choice for patients with primary adrenal tumors (33). For inoperable or partially resectable carcinoma, combination chemotherapy may offer an alternative management approach (39). However, the experience with pediatric patients is largely anedoctal. Occasionally, for the correction of hyperandrogenism, hypercortisolism, and/or hypermineralocorticoidism, steroid synthesis inhibitors such as ketoconazole and androgen, glucocorticoid, or mineralcorticoid antagonists may be required. Radiation therapy is occasionally helpful for palliation of bone metastases.

Glucocorticoid resistance

Corticotropin hypersecretion. The syndrome of glucocorticoid resistance is a rare condition resulting from partial, albeit generalized, inability of glucocorticoids to exert their effects on target tissues. The loss-of-function glucocorticoid receptor (hGR) mutation results in compensatory elevation of circulating ACTH and cortisol. Although adequate compensation is apparently achieved by elevated cortisol concentrations in the great majority of the patients described, excess ACTH secretion also results in increased production of adrenal steroids with salt-retaining activity (mineralocorticoid excess) and enhanced secretion of adrenal androgens (hyperandrogenism). Since the syndrome of familial glucocorticoid resistance was first described in 1976 (40), over 10 kindreds and few sporadic cases have been reported; however, the molecular defects of only 4 kindreds and one sporadic case have been elucidated so far (41, 42, 43, 44). Abnormalities of the hGR, primarily inactivating mutations of the ligand-binding domain or mutations leading to functional knockout of one of the two GR gene alleles, have been described (45). Recently, the genetic study of a fifth case/kindred with symptoms of hyperandrogenism and signs of marked glucocorticoid resistance, having a heterozygotic hGR mutation in the ligand-binding domain, has been carried out (46). The mutant receptor had reduced affinity for dexamethasone and decreased transcriptional activity; interestingly, it also had dominant negative activity on the wild-type receptor. Furthermore, a genetically-determined imbalanced expression of the glucocorticoid receptor isoforms (hGR{alpha} and hGRß) has been found in cultured lymphocytes from a patient with congenital generalized glucocorticoid resistance and chronic leukemia (47). Although the mechanism of action of hGR{alpha} has been extensively studied, the role of hGRß in the modulation of glucocorticoid actions remains uncertain. However, it has been recently postulated that hGRß might exert a specific dominant negative effect on transcriptional activation induced by hGR{alpha} (48, 49). Therefore, the markedly reduced hGR{alpha} and normal hGRß expression resulting in a low hGR{alpha}/hGRß ratio might be compatible with glucocorticoid resistance in this patient (47).

The spectrum of clinical manifestations of this syndrome is quite broad, varying from asymptomatic to chronic fatigue syndrome (perhaps reflecting glucocorticoid deficiency) (50) to symptoms and signs of mineralocorticoid excess, such as hypertension and/or hypokalemic alkalosis (40, 51) and hyperandrogenism. The latter can manifest as precocious puberty in children and as acne, hirsutism, menstrual irregularities, oligo, or anovulation in women and adolescents. Recently, a female newborn with ambiguous genitalia due to a combined defect of the glucocorticoid receptor and the 21-hydroxylase genes has been reported (52). In men, oligospermia and infertility have been observed, possibly as a result of disturbances in FSH regulation caused by excessive adrenal androgens (51).

The criteria for the diagnosis of primary glucocorticoid resistance are: 1) increased serum cortisol and free cortisol levels in urine without features of Cushing’s syndrome; 2) normal or increased plasma ACTH concentrations despite cortisol excess; 3) resistance to single or multiple doses of dexamethasone; 4) preservation of the normal cortisol diurnal rhythm and a stress-responsive pattern of HPA axis activity, albeit at elevated levels; and 5) evidence of glucocorticoid resistance in relatives (53).

Asymptomatic, normotensive subjects with primary glucocorticoid resistance require no treatment. Symptomatic patients should be treated with a synthetic, potent, long-acting glucocorticoid, with minimal intrinsic mineralocorticoid activity, such as dexamethasone, at a dose that would be pharmacologic for the normal population (1–3 mg/day). Untreated patients have no risk of adrenal insufficiency and do not need special precautions during surgery, illness, or other stress (53).


   Conclusion
Top
 Introduction
 Adrenal Androgen Physiology
 Etiology of Adrenal Androgen...
 Conclusion
References
 
Excess of adrenal androgens before puberty is responsible for clinical manifestations that vary with sex. In prepubertal boys the excess of adrenal androgens leads to virilization manifested as penile enlargment, hair development in androgen-dependent areas of the skin, and development of other seconadary sexual characteristics. This is defined as peripheral isosexual precocious puberty. In prepubertal girls, excess androgen leads to inappropriate virilization manifested as acne, hirsutism, and clitoromegaly. This is defined as peripheral heterosexual precocity. In both sexes, androgen excess increases height velocity and somatic development, as well as the rate of skeletal maturation. Premature epiphyseal fusion in these children frequently leads to short adult height. Thus, in children with hyperandrogenism, a prompt diagnosis is extremely important not only to achieve a rapid regression of the clinical signs of virilization, but also to prevent the late androgen-related effects on growth. In premature pubarche, the most frequent cause of adrenal hyperandrogenism in children, androgen levels are only mildly elevated and, therefore, are not accompanied by severe symptoms of androgen excess. Even in this condition, however, a careful and prolonged follow-up is necessary to monitor the eventual appearance of signs and symptoms of hyperandrogenism.

Received October 14, 1999.

Accepted October 20, 1999.


   References
Top
 Introduction
 Adrenal Androgen Physiology
 Etiology of Adrenal Androgen...
 Conclusion
 References
 

  1. Longcope C. 1986 Adrenal and gonadal androgen secretion in normal females. In: Horton R, Lobo RA, eds. Clinics in endocrinology and metabolism. Philadelphia: W.B. Saunders; 213–228.
  2. Pang SY, Legido A, Levine LS, Temeck JW, New MI. 1987 Adrenal androgen response to metyrapone, adrenocorticotropin, and corticotropin-releasing hormone stimulation in children with hypopituitarism. J Clin Endocrinol Metab. 65:282–289.[Abstract]
  3. McKerns KW. 1969 Steroidogenesis and metabolism in the adrenal cortex. In: McKerns KW, ed. Steroid hormones and metabolism. New York: Appleton-Century-Crofts; 9–30.
  4. Korth-Schutz S, Levine LS, New MI. 1976 Serum androgens in normal prepubertal and pubertal children and in children with precocious adrenarche. J Clin Endocrinol Metab. 42:117–124.[Abstract]
  5. Parker LN, Lifrak ET, Odell WD. 1983 A 60,000 molecular weight human pituitary glycopeptide stimulates adrenal androgen secretion. Endocrinology. 113:2092–2096.[Abstract]
  6. Anderson DC. 1980 The adrenal androgen-stimulating hormone does not exist. Lancet. 2:454–456.[Medline]
  7. Vale W, Spiess J, Rivier C, Rivier J. 1981 Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and ß-endorphin. Science. 213:1394–1397.[Free Full Text]
  8. Lamberts SW, Verleun T, Oosterom R, de Jong F, Hackeng WH. 1984 Corticotropin-releasing factor (ovine) and vasopressin exert a synergistic effect on adrenocorticotropin release in man. J Clin Endocrinol Metab. 58:298–303.[Abstract]
  9. Rosenfeld RS, Hellman L, Roffwarg H, Weitzman ED, Fukushima DK, Gallagher TF. 1971 Dehydroisoandrosterone is secreted episodically and synchronously with cortisol by normal man. J Clin Endocrinol Metab. 33:87–92.[Medline]
  10. Ghizzoni L, Bernasconi S, Virdis R, et al. 1994 Dynamics of 24-hour pulsatile cortisol, 17-hydroxyprogesterone, and androstenedione release in prepubertal patients with nonclassic 21- hydroxylase deficiency and normal prepubertal children. Metabolism. 43:372–377.[CrossRef][Medline]
  11. Ghizzoni L, Mastorakos G, Vottero A, Magiakou MA, Chrousos GP, Bernasconi S. 1996 Spontaneous cortisol and growth hormone secretion interactions in patients with nonclassic 21-hydroxylase deficiency (NCCAH) and control children. J Clin Endocrinol Metab. 81:482–487.[Abstract]
  12. Ghizzoni L, Mastorakos G, Street ME, et al. 1997 Spontaneous thyrotropin and cortisol secretion interactions in patients with nonclassical 21-hydroxylase deficiency and control children. J Clin Endocrinol Metab. 82:3677–3683.[Abstract/Free Full Text]
  13. Schweikert HU, Milewich L, Wilson JD. 1975 Aromatization of androstenedione by isolated human hairs. J Clin Endocrinol Metab. 40:413–417.[Abstract]
  14. Norman AW, Litwack G. 1987 Androgens. In: Norman AW, Litusassk G, eds. Hormones. San Diego: Academic Press; 483–513.
  15. Saenger P, Reiter EO. 1992 Premature adrenarche: a normal variant of puberty? J Clin Endocrinol Metab. 74:236–238.[CrossRef][Medline]
  16. Ibanez L, Virdis R, Potau N, et al. 1992 Natural history of premature pubarche: an auxological study. J Clin Endocrinol Metab. 74:254–257.[Abstract]
  17. Pang SY. 1984 Premature pubarche. Pediatr Adolesc Endocrinol. 13:173–184.
  18. Voutilainen R, Perheentupa J, Apter D. 1983 Benign premature adrenarche: clinical features and serum steroid levels. Acta Paediatr Scand. 72:707–711.[Medline]
  19. Zhang LH, Rodriguez H, Ohno S, Miller WL. 1995 Serine phosphorylation of human P450c17 increases 17,20-lyase activity: implications for adrenarche and the polycystic ovary syndrome. Proc Natl Acad Sci USA. 92:10619–10623.[Abstract/Free Full Text]
  20. Ghizzoni L, Virdis R, Ziveri M, et al. 1989 Adrenal steroid, cortisol, adrenocorticotropin, and ß-endorphin responses to human corticotropin-releasing hormone stimulation test in normal children and children with premature pubarche. J Clin Endocrinol Metab. 69:875–880.[Abstract]
  21. Morris AH, Reiter EO, Geffner ME, Lippe BM, Itami RM, Mayes DM. 1989 Absence of nonclassical congenital adrenal hyperplasia in patients with precocious adrenarche. J Clin Endocrinol Metab. 69:709–715.[Abstract]
  22. New M, Ghizzoni L, Speiser PW. 1996 Update on congenital adrenal hyperplasia. In: Lifshitz F, eds. Pediatric endocrinology, 3rd ed. New York: Marcel Dekker; 305–320.
  23. Dacou-Voutetakis C, Dracopoulou M. 1999 High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche. J Clin Endocrinol Metab. 84:1570–1574.[Abstract/Free Full Text]
  24. de Peretti E, Forest MG. 1976 Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in human: the use of a sensitive radioimmunoassay. J Clin Endocrinol Metab. 43:982–991.[Abstract]
  25. Ibanez L, Potau N, Virdis R, et al. 1993 Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab. 76:1599–1603.[Abstract]
  26. Oppenheimer E, Linder B, DiMartino-Nardi J. 1995 Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans. J Clin Endocrinol Metab. 80:614–618.[Abstract]
  27. Ibanez L, Potau N, Zampolli M, et al. 1996 Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J Clin Endocrinol Metab. 81:1237–1243.[Abstract]
  28. Vuguin P, Linder B, Rosenfeld RG, Saenger P, DiMartino-Nardi J. 1999 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. 84:2037–2042.[Abstract/Free Full Text]
  29. Ibanez L, Potau N, Francois I, de Zegher F. 1998 Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Metab. 83:3558–3562.[Abstract/Free Full Text]
  30. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. 1995 Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 96:801–810.
  31. Flack MR, Chrousos GP. 1996 Neoplasms of the adrenal cortex. In: Holland R, ed. Cancer medicine, 4th ed. New York: Lea and Fibinger; 1563–1570.
  32. Chudler RM, Kay R. 1989 Adrenocortical carcinoma in children. Urol Clin North Am. 16:469–479.[Medline]
  33. Latronico AC, Chrousos GP. 1997 Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab. 82:1317–1324.[Free Full Text]
  34. Kaplan SA. 1979 Disorders of the adrenal cortex. I. Pediatr Clin North Am. 26:65–76.[Medline]
  35. Luton JP, Cerdas S, Billaud L, et al. 1990 Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy (see comments). N Engl J Med. 322:1195–1201.[Abstract]
  36. Liu J, Heikkila P, Kahri AI, Voutilainen R. 1996 Expression of the steroidogenic acute regulatory protein mRNA in adrenal tumors and cultured adrenal cells. J Endocrinol. 150:43–50.[Abstract/Free Full Text]
  37. Wong M, Ramayya MS, Chrousos GP, Driggers PH, Parker KL. 1996 Cloning and sequence analysis of the human gene encoding steroidogenic factor 1. J Mol Endocrinol. 17:139–147.[Abstract/Free Full Text]
  38. Muscatelli F, Strom TM, Walker AP, et al. 1994 Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature. 372:672–676.[CrossRef][Medline]
  39. Schlumberger M, Brugieres L, Gicquel C, Travagli JP, Droz JP, Parmentier C. 1991 5-Fluorouracil, doxorubicin, and cisplatin as treatment for adrenal cortical carcinoma. Cancer. 67:2997–3000.[CrossRef][Medline]
  40. Vingerhoeds AC, Thijssen JH, Schwarz F. 1976 Spontaneous hypercortisolism without Cushing’s syndrome. J Clin Endocrinol Metab. 43:1128–1133.[Abstract]
  41. Hurley DM, Accili D, Stratakis CA, et al. 1991 Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 87:680–686.
  42. Malchoff DM, Brufsky A, Reardon G, et al. 1993 A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 91:1918–1925.
  43. Karl M, Lamberts SW, Detera-Wadleigh SD, et al. 1993 Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab. 76:683–689.[Abstract]
  44. Karl M, Lamberts SW, Koper JW, et al. 1996 Cushing’s disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation. Proc Assoc Am Physicians. 108:296–307.[Medline]
  45. Chrousos GP, Detera-Wadleigh SD, Karl M. 1993 Syndromes of glucocorticoid resistance. Ann Intern Med. 119:1113–1124.[Abstract/Free Full Text]
  46. Vottero A, Combe H, Lecomte P, Longui CA, Chrousos GP. 1999 A novel mutation of the glucocorticoid receptor in familial glucocorticoid resistance. Proc 81st Annual Meeting of The Endocrine Society, San Diego, CA; 90.
  47. Shahidi H, Vottero A, Stratakis CA, et al. 1999 Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia. Biochem Biophys Res Commun. 254:559–565.[CrossRef][Medline]
  48. Bamberger CM, Bamberger AM, de Castro M, Chrousos GP. 1995 Glucocorticoid receptor ß, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest. 95:2435–2441.
  49. Oakley RH, Webster JC, Sar M, Parker CRJ, Cidlowski JA. 1997 Expression and subcellular distribution of the ß-isoform of the human glucocorticoid receptor. Endocrinology. 138:5028–5038.[Abstract/Free Full Text]
  50. Bronnegard M, Werner S, Gustafsson JA. 1986 Primary cortisol resistance associated with a thermolabile glucocorticoid receptor in a patient with fatigue as the only symptom. J Clin Invest. 78:1270–1278.
  51. Lamberts SW, Koper JW, Biemond P, den Holder FH, de Jong FH. 1992 Cortisol receptor resistance: the variability of its clinical presentation and response to treatment. J Clin Endocrinol Metab. 74:313–321.[Abstract]
  52. Mendonca B, Leite MV, Bachega TA, Billerbeck AEC, Latronico A. 1999 Familial glucocorticoid resistance due to a novel mutation in the glucocorticoid receptor gene associated with a heterozygous large conversion of 21-hydroxylase gene causing female pseudohermaphroditism. Proc 81st Annual Meeting of The Endocrine Society, San Diego, CA; 273.
  53. de Castro M, Chrousos GP. 1997 Glucocorticoid resistance. Curr Ther Endocrinol Metab. 6:188–9:188–189.[Medline]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals