Adrenomedullary Dysplasia and Hypofunction in Patients with Classic 21-Hydroxylase Deficiency
Deborah P. Merke, M.D., George P. Chrousos, M.D., Graeme Eisenhofer, Ph.D., Martina Weise, M.D., Margaret F. Keil, R.N., Alan D. Rogol, M.D., Ph.D., Judson J. Van Wyk, M.D., and Stefan R. Bornstein, M.D.
Background Glucocorticoids are essential for the normal developmentand functioning of the adrenal medulla. Whether adrenomedullarystructure and function are normal in patients with congenitaladrenal hyperplasia is not known.
Methods We measured plasma and urinary catecholamines and plasmametanephrines in 38 children with congenital adrenal hyperplasiadue to 21-hydroxylase deficiency (25 children with the salt-wastingform and 13 with the simple virilizing form), 39 age-matchednormal subjects, and 20 patients who had undergone bilateraladrenalectomy. Adrenal specimens obtained from three other patientswith 21-hydroxylase deficiency who had undergone bilateral adrenalectomyand specimens obtained at autopsy from eight other patientswere examined histologically.
Results Plasma epinephrine and metanephrine concentrations andurinary epinephrine excretion were 40 to 80 percent lower inthe patients with congenital adrenal hyperplasia than in thenormal subjects (P< 0.05), and the values were lowest inthe patients with the most severe deficits in cortisol production.Urinary epinephrine excretion and plasma epinephrine concentrationswere at or below the limit of detection of the assay in 8 (21percent) of the patients with congenital adrenal hyperplasiaand in 19 (95 percent) of the patients who had undergone adrenalectomy.In the group of patients with congenital adrenal hyperplasia,plasma epinephrine and metanephrine concentrations and urinaryepinephrine excretion were approximately 50 percent lower inthose who had been hospitalized for adrenal crises than in thosewho had not. In three patients with congenital adrenal hyperplasiawho had undergone bilateral adrenalectomy, the formation ofthe adrenal medulla was incomplete, and electron-microscopicalstudies revealed a depletion of secretory vesicles in chromaffincells.
Conclusions Congenital adrenal hyperplasia compromises boththe development and the functioning of the adrenomedullary system.
Congenital adrenal hyperplasia is characterized clinically byprenatal virilization and genital ambiguity in newborn girls,postnatal virilization in both boys and girls, and adrenal insufficiencywith or without salt wasting.1,2,3 Biochemically, the disorderis characterized by impaired production of cortisol with orwithout impaired production of aldosterone, chronic stimulationof the adrenal cortex by corticotropin, and overproduction ofcortisol precursors and androgens. The most common cause ofcongenital adrenal hyperplasia is 21-hydroxylase deficiency,with an incidence of approximately 1 case per 15,000 live birthsworldwide.1 Despite adequate treatment with glucocorticoid andmineralocorticoid replacement, children with the classic orsevere form of 21-hydroxylase deficiency remain prone to adrenalcrises, hypoglycemia, and cardiovascular collapse in responseto febrile illnesses or other stressful circumstances, evenwhen their serum electrolyte concentrations are normal.4,5
The two adrenal stress systems, the cortisol-producing cortexand the catecholamine-producing medulla, are closely linkedontogenetically, anatomically, and functionally.6,7,8,9,10 Glucocorticoidsare important in the development and regulation of the adrenalmedulla. We evaluated adrenomedullary function in patients withcongenital adrenal hyperplasia due to 21-hydroxylase deficiency,in age-matched normal subjects, and in patients who had undergonebilateral adrenalectomy. We performed histologic evaluationof adrenal specimens obtained from three patients with congenitaladrenal hyperplasia who underwent bilateral adrenalectomy andspecimens obtained at autopsy from eight age-matched patients.
Methods
Study Subjects
From November 1998 through April 2000, we studied 38 patients(24 boys and 14 girls; age range, 4 to 16 years) with classic21-hydroxylase deficiency, 39 normal subjects (20 boys and 19girls; age range, 5 to 17 years), and 20 patients (5 men and15 women; age range, 26 to 66 years) who had undergone bilateraladrenalectomy because of familial pheochromocytoma (9 patients)or Cushing's syndrome (11).
The 38 patients with congenital adrenal hyperplasia were classifiedas having the salt-wasting or simple virilizing form of thedisorder (Table 1). The 18 patients who had had a neonatal crisiswith documented hyperkalemia and hyponatremia were classifiedas having the salt-wasting form, and the 10 patients (8 boysand 2 girls) in whom early virilization was diagnosed at anolder age (mean age at diagnosis, 4 years; range, 2 to 6) wereclassified as having the simple virilizing form. In 10 patients,treatment was started at birth, thus preventing confirmationof the salt-wasting phenotype. Seven of these patients wereclassified as having the salt-wasting form of the disorder onthe basis of a history of markedly elevated plasma renin activityor a salt-wasting adrenal crisis; the other three were classifiedas having the simple virilizing form. The number of adrenalcrises requiring hospitalization was obtained from parentalreports and medical records.
Table 1. Characteristics of Children with the Salt-Wasting or Simple Virilizing Form of Congenital Adrenal Hyperplasia.
We performed histologic studies of adrenal glands from threepatients with congenital adrenal hyperplasia who had undergonebilateral adrenalectomy because of difficult-to-control hyperandrogenism,severe salt wasting, or both (a 3-year-old girl,11 a 5-year-oldboy, and a 16-year-old girl12) and from eight patients withno known adrenal disease who had died of sepsis or trauma (agerange, 4 to 15 years). The weight of the adrenal glands fromthe 3-, 5-, and 16-year-old patients with congenital adrenalhyperplasia (5, 26, and 52 g, respectively) was greater thanthe normal weight for their age,13 whereas the weight of theadrenal glands from the other eight patients (range, 3 to 6g) was appropriate for their age. Before undergoing adrenalectomy,the three patients with congenital adrenal hyperplasia had receiveddoses of hydrocortisone ranging from 15 to 30 mg per squaremeter of body-surface area per day, and they had received multiplecourses of higher doses of glucocorticoids in the year beforesurgery, in an attempt to control excess androgen secretion.
The study was approved by the institutional review board atthe National Institute of Child Health and Human Developmentand at each participating center. Each patient or a parent gavewritten informed consent, and children over the age of sevenyears gave their assent.
Hormone Measurements
At approximately 8 a.m., samples of blood were drawn into 10-mlheparinized tubes through an intravenous cannula in the forearm.In the patients who had congenital adrenal hyperplasia or whohad undergone adrenalectomy, the samples were obtained beforethe usual morning doses of hydrocortisone and fludrocortisone.All the subjects (or their parents on their behalf) had beeninstructed to avoid the use of acetaminophen, which interfereswith the plasma normetanephrine assay, for at least five daysbefore the blood samples were obtained. Once the cannula hadbeen inserted, the subjects rested in a supine position fora minimum of 15 minutes before the blood was collected. Plasmawas stored at –70°C until the assays were performed.Plasma epinephrine, norepinephrine, metanephrine, and normetanephrinewere measured by liquid chromatography with electrochemicaldetection, as described elsewhere.14,15 Twenty-four-hour urinespecimens were obtained for catecholamine measurements whilethe patients were taking their usual doses of glucocorticoidsand mineralocorticoids. Urinary epinephrine and norephinephrinewere measured by liquid chromatography (Mayo Medical Laboratories,Rochester, Minn.).16
Endogenous cortisol production (which reflects the adrenocorticalreserve) was evaluated by obtaining from the medical recordthe maximal plasma cortisol concentration recorded either 60minutes after the intravenous administration of 250 µgof cosyntropin (in 28 patients) or when plasma corticotropinand 17-hydroxyprogesterone concentrations were elevated becausehydrocortisone had been withheld (in 10). Plasma cortisol wasmeasured by fluorescence polarization immunoassay (TDX-FLX,Abbott Laboratories, Abbott Park, Ill.). Plasma 17-hydroxyprogesteroneand corticotropin were measured by radioimmunoassay (HazeltonLaboratories, Vienna, Va.).
Immunohistochemical Studies
The adrenal glands were fixed in 4 percent formalin and embeddedin paraffin. Thin sections (6 µm) were cut from the largestdiameter of the gland, so that they contained both cortex andmedulla. The sections were deparaffinized in xylene and hydratedin ethanol. Endogenous peroxidase activity was stopped by incubatingthe sections with 1.5 percent hydrogen peroxide and 10 percentmethanol in phosphate-buffered saline for 10 minutes.
Adrenal chromaffin cells were stained with antibodies againstchromogranin A (rabbit antihuman antiserum IgG antibodies, Dako,Hamburg, Germany) and tyrosine hydroxylase (Boehringer Mannheim,Mannheim, Germany), as previously described.7 Bound antibodieswere detected by the linked streptavidin–biotin–peroxidasemethod (Dako), and the enzyme reaction was visualized with 3-amino-ethylcarbazole(Dianova, Hamburg, Germany). Monoclonal mouse antibodies againstimmunoglobulin were used as a negative control. All slides werecounterstained with hematoxylin, rinsed in water, dehydrated,and mounted.
Electron-Microscopical Studies
Adrenal tissue was dissected and fixed with 2 percent formaldehydeand 2 percent glutaraldehyde in 0.1 M phosphate buffer at apH of 7.3 for three hours. Tissue slices were then fixed for90 minutes with 2 percent osmium solution in 0.1 M cacodylatebuffer at a pH of 7.3, dehydrated in ethanol, and embedded inepoxy resin. Ultrathin sections were stained with uranyl acetateand lead citrate and were examined by electron microscopy.
Statistical Analysis
Two-sided Student's t-tests, chi-square tests, and analysisof variance with Scheffé's test were used to comparethe results among the groups. Jonckheere's test was performedto analyze trends among the groups. Values are expressed asmeans ±SD, unless otherwise specified.
Results
Clinical Findings
At the time of the study, there were no significant differencesin age or in hydrocortisone and fludrocortisone doses betweenthe group of patients with the salt-wasting form of congenitaladrenal hyperplasia and the group with the simple virilizingform (Table 1). In both groups, the adrenocortical reserve wasmarkedly reduced, as assessed by the maximal recorded plasmacortisol concentration (normal value, >18 µg per deciliter[497 nmol per liter]). However, the level of adrenal cortisolproduction was significantly lower in the patients with thesalt-wasting form than in those with the simple virilizing form.
The mean number of adrenal crises requiring hospitalizationand the mean number of hospitalizations during the first twoyears after diagnosis were significantly higher in the groupwith the salt-wasting form than in the group with the simplevirilizing form (Table 1). The distinction between the two formsof the disease was somewhat arbitrary, however, because twoboys initially classified as having the simple virilizing formof congenital adrenal hyperplasia on the basis of their ageat the time of diagnosis (two years and five months in one case,and three years in the other) subsequently had an adrenal crisiswith documented hyponatremia and hyperkalemia during an acuteviral illness.
Biochemical Findings
The patients with congenital adrenal hyperplasia and those withother disorders who had undergone bilateral adrenalectomy hadsignificantly lower plasma epinephrine and metanephrine concentrationsand urinary epinephrine excretion than the normal subjects (Table 2).The extent of the hormonal deficiencies was associated withthe severity of adrenocortical dysfunction (the deficiencieswere smallest in the group with the simple virilizing form,intermediate in the group with the salt-wasting form, and largestin the adrenalectomy group; P<0.001). Values for plasma epinephrineand 24-hour urinary epinephrine excretion were at or below thethreshold of detection in 19 of the 20 patients who had undergoneadrenalectomy (95 percent) and in 8 of the 38 patients withcongenital adrenal hyperplasia (21 percent); all the normalsubjects had detectable values (P<0.001 for the comparisonof each group of patients with the normal subjects).
Table 2. Mean (±SD) Plasma Concentrations and Urinary Excretion of Epinephrine, Metanephrine, Norepinephrine, and Normetanephrine in Children with Congenital Adrenal Hyperplasia (CAH), Age-Matched Normal Subjects, and Patients Who Had Undergone Bilateral Adrenalectomy.
Plasma norepinephrine concentrations and urinary norepinephrineexcretion were significantly higher in the patients who hadundergone adrenalectomy than in the normal subjects. However,the patients with congenital adrenal hyperplasia did not haveincreased values for plasma or urinary norepinephrine. Plasmanormetanephrine concentrations were lower in the patients withcongenital adrenal hyperplasia and in the patients who had undergoneadrenalectomy than in the normal subjects, reflecting substantialproduction of the O -methylated metabolite in the adrenal medulla.17,18The patients who had a history of an adrenal crisis requiringhospitalization had lower plasma catecholamine concentrationsthan the patients who had never been hospitalized for an adrenalcrisis (plasma epinephrine concentration, 6±4 vs. 12±10pg per milliliter [33±22 vs. 66±55 pmol per liter];P=0.05; plasma metanephrine concentration, 13±7 vs. 22±13pg per milliliter [66±36 vs. 112±66 pmol per liter];P=0.03; and urinary epinephrine excretion, 0.6±0.6 vs.1.2±0.9 µg per day [3.3±3.3 vs. 6.6±4.9nmol per day]; P=0.05).
Histologic Findings
Light-microscopical studies of adrenal glands from three patientswith 21-hydroxylase deficiency showed adrenocortical hyperplasiaand poorly defined zones, with an irregular zona glomerulosa,zona fasciculata–like cells that reached the capsule,and extensive intermingling of cortical and chromaffin cells(Figure 1A and Figure 1B). Immunostaining with anti–chromograninA showed that the formation of the adrenal medulla in the centerof the gland was incomplete, with single cells and islets ofchromaffin cells remaining within the adrenal cortex (Figure 1B).Immunostaining with antibodies against tyrosine hydroxylaseshowed smaller amounts of the enzyme in chromaffin cells fromthe patients with 21-hydroxylase deficiency than in chromaffincells from patients studied at autopsy (Figure 1C and Figure 1D).
Figure 1. Immunostaining of Tissue from a Normal Adrenal Gland (Panels A and C) and an Adrenal Gland from a Patient with Classic 21-Hydroxylase Deficiency (Panels B and D).
Panel A shows well-defined zones as well as minimal intermingling of the chromaffin and cortical cells (arrows) in the normal adrenal gland (x40). Panel B shows hyperplasia, poorly defined zones, and pronounced intermingling of the chromaffin and cortical cells (arrows) in the adrenal gland from a patient with 21-hydroxylase deficiency (x40). Chromaffin cells were stained with anti–chromogranin A. Panel C shows staining with anti–tyrosine hydroxylase, with an irregular border between the adrenal cortex and the medulla (arrow), in normal adrenal medulla (x400), and Panel D shows reduced amounts of the enzyme in islands of chromaffin cells (arrows) from a patient with congenital adrenal hyperplasia (x400). In all four panels, the reactions were visualized with 3-amino-ethylcarbazole and hematoxylin (reddish-brown). M denotes medulla, ZR zona reticularis, ZF zona fasciculata, ZG zona glomerulosa, CAP capsule, CV central vein, and C cortex.
Electron-Microscopical Findings
On the ultrastructural level, the normal adrenocortical cellscontained ample smooth endoplasmic reticulum, with normal mitochondrialstructure characterized by elongated tubulolamellar cristaein glomerulosa cells and round tubulovesicular cristae in zonafasciculata and zona reticularis cells (Figure 2A). In the patientswith 21-hydroxylase deficiency, the zona glomerulosa was irregular,and the subcellular adrenocortical structure was characterizedby an abnormally large amount of cytoplasm with dilated smoothendoplasmic reticulum, large, round mitochondria, and poorlydeveloped internal membranes (Figure 2B).
Figure 2. Electron Micrographs of a Normal Adrenal Gland (Panels A and C) and an Adrenal Gland from a Patient with 21-Hydroxylase Deficiency (Panels B and D), with Uranyl Acetate and Lead Citrate Staining.
Unlike normal adrenocortical cells (Panel A), those in a patient with 21-hydroxylase deficiency (Panel B) contain dilated smooth endoplasmic reticulum (SER) and large, round mitochondria (MIT), with sparse tubulovesicular internal membranes (arrows). Chromaffin cells with normal cytoplasm (Panel C) are filled with densely grouped catecholamine-containing secretory vesicles (CV), 50 to 450 nm in the greatest diameter. The majority of cells contain secretory vesicles with round or elongated, medium-density granules and a granular substructure of epinephrine-containing vesicles. In the adrenal gland from the patient with 21-hydroxylase deficiency, there is a conspicuous depletion of secretory vesicles, and the remaining vesicles are predominantly norepinephrine-containing, electron-dense vesicles lying in large lucent vacuoles (Panel D). The empty vacuoles are not secretory vesicles but vesiculated, rough endoplasmic reticulum (arrows). In all four panels, the bar represents 0.5 µm. LIP denotes liposomes, NUC nucleus, and ERY erythrocyte.
The chromaffin cells in the normal adrenal glands had the typicalultrastructural features of neuroendocrine cells, with amplemembrane-bound secretory vesicles and dense-core vesicles approximately50 to 450 nm in their greatest diameter (Figure 2C). In thenormal adrenal medulla, there are two major types of vesicles:large, round or elongated, epinephrine-containing vesicles ofmedium density with a particulate substructure, and small, norepinephrine-containingvesicles of high density within large, lucent vacuoles (Figure 2C).In the patients with 21-hydroxylase deficiency, the secretoryvesicles were depleted, and the remaining vesicles were primarilynorepinephrine-containing, high-density vesicles within large,lucent vacuoles (Figure 2D). The chromaffin cells were frequentlyintermingled with adrenocortical cells in the cortex.
Discussion
We found that patients with classic 21-hydroxylase deficiencyhad both adrenomedullary dysfunction, characterized by reducedproduction of epinephrine, metanephrine, and normetanephrine,and major structural changes in the adrenal medulla, characterizedby dysplasia, reduced expression of tyrosine hydroxylase, anddepletion of epinephrine-containing secretory vesicles. Thepatients with the most severe phenotype, associated with saltwasting and a history of adrenal crises requiring hospitalization,had the lowest levels of adrenal production of epinephrine andmetanephrine.
Chromaffin precursor cells start migrating into the adrenalanlagen in the sixth week of gestation and differentiate intomature chromaffin cells under the influence of adrenocorticalsteroids.19 High intra-adrenal glucocorticoid concentrationsare necessary for the induction of phenylethanolamine N-methyltransferase,the enzyme that converts norepinephrine to epinephrine, andtherefore for adrenal epinephrine synthesis.20,21 The low plasmaand urinary epinephrine values in our patients with congenitaladrenal hyperplasia may have been due to the lack of high intra-adrenalglucocorticoid concentrations at the time of the study or tofaulty embryogenesis.
In normal adrenal glands, adrenocortical cells are frequentlyseen in the medulla, but outgrowths of chromaffin cells in thecortex are uncommon.6,7 In our study, the intermingling of thetwo types of endocrine cells was more pronounced in the patientswith congenital adrenal hyperplasia than in the normal subjects,suggesting that congenital adrenal hyperplasia is caused bya developmental defect in the formation of the adrenal medulla.
In humans, epinephrine constitutes over 80 percent of adrenalcatecholamine secretion,18 and epinephrine secretion can increaseby a factor of more than 300 under stressful conditions.22 Patientswith acquired secondary adrenal insufficiency have diminishedbasal epinephrine secretion, even with glucocorticoid-replacementtherapy, suggesting that a high intra-adrenal glucocorticoidconcentration is necessary for the maintenance of adrenal epinephrinesynthesis.23 Compensatory increases in sympathetic-nerve activityand norepinephrine secretion have been reported in patientswith Addison's disease23 and in those who have undergone bilateraladrenalectomy,17 but these changes did not occur in our patientswith congenital adrenal hyperplasia.
Over 90 percent of circulating metanephrine and up to 40 percentof circulating normetanephrine are produced from epinephrineand norepinephrine that have leaked from storage vesicles intothe cytoplasm of chromaffin cells.17,18 This process is independentof exocytotic catecholamine release. Thus, unlike the low plasmaand urinary epinephrine values, which reflect decreased adrenomedullarysecretion of epinephrine, the low plasma concentrations of metanephrineand normetanephrine in patients with congenital adrenal hyperplasiareflect decreased adrenomedullary stores of both epinephrineand norepinephrine. This finding is consistent with the observationthat adrenal epinephrine and norepinephrine are reduced in micewith 21-hydroxylase deficiency,10 but it contrasts with theobservation that adrenal epinephrine is decreased and adrenalnorepinephrine increased in animals with reduced glucocorticoidsynthesis.24 Thus, decreased adrenomedullary secretion of epinephrinein patients with 21-hydroxylase deficiency may result not onlyfrom reduced phenylethanolamine N-methyltransferase activitybut also from an overall decrease in catecholamine synthesis,which in turn may be related to the general changes we observedin the structural development of the adrenal medulla.
In our study, the group of patients with the salt-wasting formof adrenal hyperplasia had a larger mean number of hospitalizationsdue to adrenal crises than the group with the simple virilizingform. Adequate glucocorticoid and mineralocorticoid replacementdid not prevent hospitalization, suggesting that epinephrinedeficiency may have had a role. However, noncompliance withtreatment, inadequate doses of glucocorticoids when there wasan intercurrent illness, or the physician's unease with outpatienttreatment may have contributed to the decision to hospitalizea child.
Our findings have important clinical implications with regardto bilateral adrenalectomy as a treatment option for patientswith congenital adrenal hyperplasia. Adrenalectomy has beenproposed for selected patients in whom the disorder is difficultto control with conventional medical treatment.25,26 Opponentsof this proposal argue that surgery may result in loss of theprotective function of the adrenal medulla in times of stress.Our findings indicate that this protective function may alreadybe absent in the most severe cases; thus, bilateral adrenalectomymay not pose this risk.
We conclude that congenital adrenal hyperplasia due to 21-hydroxylasedeficiency not only affects the hypothalamic–pituitary–adrenalaxis and the renin–angiotensin–aldosterone systembut also severely compromises adrenomedullary secretion. Thereduction in epinephrine secretion is probably due to a combinationof the lack of intra-adrenal cortisol secretion and abnormaladrenomedullary formation.
We are indebted to the patients and their families for participatingin this study: to Ms. Donna Peterson for assistance in datamanagement; to Dr. Robert Wesley for assistance in the statisticalanalysis; to the members of the nursing staff at the WarrenGrant Magnuson Clinical Center who assisted in the care of thepatients; and to Ms. Zahra Rassouli, Dr. Mones Abu-Asab, andMs. Courtney Holmes for technical assistance.
Source Information
From the Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Md. (D.P.M.); the Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Md. (D.P.M., G.P.C., M.W., M.F.K., S.R.B.); the Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, Bethesda, Md. (G.E.); the University of Virginia Health System, Charlottesville (A.D.R.); and the Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill (J.J.V.W.).
Address reprint requests to Dr. Merke at the National Institutes of Health, Bldg. 10, Rm. 13S260, 10 Center Dr., MSC 1932, Bethesda, MD 20892-1932.
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Weise, M., Mehlinger, S. L., Drinkard, B., Rawson, E., Charmandari, E., Hiroi, M., Eisenhofer, G., Yanovski, J. A., Chrousos, G. P., Merke, D. P.
(2004). Patients with Classic Congenital Adrenal Hyperplasia Have Decreased Epinephrine Reserve and Defective Glucose Elevation in Response to High-Intensity Exercise. J. Clin. Endocrinol. Metab.
89: 591-597
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Coutant, R., Maurey, H., Rouleau, S., Mathieu, E., Mercier, P., Limal, J. M., Le Bouil, A.
(2003). Defect in Epinephrine Production in Children with Craniopharyngioma: Functional or Organic Origin?. J. Clin. Endocrinol. Metab.
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Speiser, P. W., White, P. C.
(2003). Congenital Adrenal Hyperplasia. NEJM
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Van Wyk, J. J., Ritzen, E. M.
(2003). The Role of Bilateral Adrenalectomy in the Treatment of Congenital Adrenal Hyperplasia. J. Clin. Endocrinol. Metab.
88: 2993-2998
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Merke, D. P., Fields, J. D., Keil, M. F., Vaituzis, A. C., Chrousos, G. P., Giedd, J. N.
(2003). Children with Classic Congenital Adrenal Hyperplasia Have Decreased Amygdala Volume: Potential Prenatal and Postnatal Hormonal Effects. J. Clin. Endocrinol. Metab.
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Stikkelbroeck, N. M. M. L., Oyen, W. J. G., van der Wilt, G.-J., Hermus, A. R. M. M., Otten, B. J.
(2003). Normal Bone Mineral Density and Lean Body Mass, but Increased Fat Mass, in Young Adult Patients with Congenital Adrenal Hyperplasia. J. Clin. Endocrinol. Metab.
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Weise, M., Eisenhofer, G., Merke, D. P.
(2002). Pubertal and Gender-Related Changes in the Sympathoadrenal System in Healthy Children. J. Clin. Endocrinol. Metab.
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Joint LWPES/ESPE CAH Working Group,
(2002). Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology. J. Clin. Endocrinol. Metab.
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Charmandari, E., Eisenhofer, G., Mehlinger, S. L., Carlson, A., Wesley, R., Keil, M. F., Chrousos, G. P., New, M. I., Merke, D. P.
(2002). Adrenomedullary Function May Predict Phenotype and Genotype in Classic 21-Hydroxylase Deficiency. J. Clin. Endocrinol. Metab.
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Charmandari, E., Weise, M., Bornstein, S. R., Eisenhofer, G., Keil, M. F., Chrousos, G. P., Merke, D. P.
(2002). Children with Classic Congenital Adrenal Hyperplasia Have Elevated Serum Leptin Concentrations and Insulin Resistance: Potential Clinical Implications. J. Clin. Endocrinol. Metab.
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Charmandari, E, Brook, C G D, Hindmarsh, P C
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Merke, D. P., Bornstein, S. R., Avila, N. A., Chrousos, G. P.
(2002). Future Directions in the Study and Management of Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. ANN INTERN MED
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Zuckerman-Levin, N., Tiosano, D., Eisenhofer, G., Bornstein, S., Hochberg, Z.'e.
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Roden, M., Raffesberg, W., Raber, W., Bernroider, E., Niederle, B., Waldhausl, W., Gasic, S.
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