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Pediatric Endocrinology Unit (G.P., C.Th.), Physiology Laboratory (C.Tr.), and Université René Descartes and Pediatric Surgery Department (S.L.-J., C.N.-F.), Hôpital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris, 75743 Paris, France; Biochimie Endocrinienne et Moléculaire, Hôpital Debrousse, INSERM, U-329 (V.T., Y.M.), 69322 Lyon, France; and Université René Descartes and Pediatric Endocrinology Unit, Fondation-Hôpital Saint Joseph (R.B.), 75674 Paris, France
Address all correspondence and requests for reprints to: Dr. R. Brauner, 211 avenue Daumesnil, 75012 Paris, France. E-mail: raja.brauner{at}wanadoo.fr.
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Abstract |
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The severity of the genetic defects and the clinical-laboratory features are well correlated. Genotyping, combined with neonatal screening and optimal medical and surgical treatment, can help in the management of CAH.
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Introduction |
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The functional gene (CYP21) is located within the human leukocyte antigen gene region on the short arm of chromosome 6 in tandem with a nonfunctional pseudogene (CYP21P). The CYP21 and CYP21P genes each have 10 exons and are very similar. The exons are about 98% identical, whereas the intronic sequences are about 96% identical. This genomic structure can lead to misalignment during meiosis, which may result in recombination between the CYP21 and CYP21P genes. Most patients are compound heterozygotes, having different mutations of the CYP21 gene on each allele. The clinical expression of CAH is reported to be correlated with the less severely mutated allele (6). Some studies have analyzed the correlation between genotype and phenotype (7, 8, 9, 10, 11, 12, 13). The clinical care of these patients is an important issue because of the risk of hypoglycemia, circulatory collapse, and electrolyte disorders in young patients with the classical form and reduced final height in older patients with either the classical or nonclassical forms.
All 68 cases of CAH due to 21-hydroxylase deficiency followed by us, whose genotype has been established, have been analyzed. Their clinical-laboratory features, treatment, puberty, and final height are described. The patients were classified according to genotype, and these parameters of the groups were compared.
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Patients and Methods |
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This study is the result of close collaboration between experts of several disciplines. A total of 68 patients (28 males) with CAH due to 21-hydroxylase deficiency were studied. Their clinical follow-up and any surgical reconstruction were performed by the same observers at the pediatric endocrinology and surgery departments, and hormones were assayed at the physiology laboratory of Hôpital Necker-Enfants Malades (Paris, France). All patients were genotyped, as were the parents and siblings of 39 of them, by the molecular biologists at Hôpital Debrousse (Lyon, France). The patients were first seen between April 1981 and December 1997 and were monitored for at least 5 yr. They were classified according to the residual enzyme activity, determined in vitro (2). The enzyme activity was zero in group 0, 0–1% of normal in group A, 2% in group B, and 30–50% in group C. The enzyme activity of the group D patients remains unknown, and these patients were analyzed separately.
Clinical analysis
Genital examinations were performed only by the surgeons, usually at birth, at surgery, and after the first menstruation. The anatomy of the genitalia was assessed by one of us (C.N.-F.) using 2 classifications. One assessed the external genitalia (14), and the other assessed vaginal masculinization (15). Type A patients had a large vagina with a uretro-vaginal communication close to the perineum. Type B patients had a uretro-vaginal communication halfway up the vertical urethra. Type C patients (rare) had a uretro-vaginal communication near the bladder neck. The vagina was short and atretic in type B and C patients. Heights were expressed as the SD score (SDS) for chronological age (16). Target heights were calculated from parental heights (17). Bone age was assessed by one of us (R.B.) (18) routinely at diagnosis in the patients with premature pubarche, at the onset of puberty, or if the growth rate was abnormal and unexplained by difficulties in equilibration. Pubarche was considered premature when it started before 8 yr in females and 9 yr in males. The onset of puberty was defined by the onset of breast development in females and increased testicular volume in males. The ages at onset of puberty and menarche, final height, and pubertal growth were determined, as was the frequency of severe complications. Final height was reached by 16 patients with the classical form, by 8 group C patients, and by 3 group D patients. Pubertal growth was the increase in height between the onset of puberty and the final height (16).
Oral 9
-fludrocortisone (micrograms per day) was given in the morning and the evening. It was associated with sodium chloride supplements at 1–2 g/d (17–34 mEq/d) from birth to 2 yr of age. Oral hydrocortisone (milligrams per square meter of height per day) was given three times a day until the patient was about 3 yr old and went to playschool, after which it was given in the morning and evening. Parents were trained and instructed to give double the dose of hydrocortisone if the patient was suffering from an intercurrent disease or to replace the oral 9-fludrocortisone and hydrocortisone with injectable forms if the patient showed any gastrointestinal disorders or was under general anesthesia. They had the prescription for the injectable form at home and were asked to call us if the patient was suffering from any gastrointestinal disorder. A hydrocortisone supplement was also given in cases of stress or intensive physical effort.
Hormonal analysis
The 16 patients seen most recently underwent neonatal screening (19) performed through the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant. Blood samples were taken in the morning, once a day, during treatment. The plasma concentrations of 17-hydroxyprogesterone (17OHP), testosterone (T), and plasma renin activity were measured at the initial evaluation, and 21 patients in groups B, C, and D underwent a short-term ACTH stimulation test (0.25 mg, im). Patients were diagnosed as having 21-hydroxylase deficiency on the basis of their plasma 17OHP concentrations, basally or 60 min post-ACTH stimulation (>30 nmol/liter) (20). The initial plasma 17OHP and T concentrations were not available for 8 patients diagnosed elsewhere. The frequency of blood sampling varied according to the chronological age of the patient. Samples were taken every week during the first month of life and then every month until 3 months of age, every 3 months until 2 yr of age, and every 6 months until the end of growth and puberty. The dose of 9-fludrocortisone was adjusted according to the plasma renin activity, and the dose of hydrocortisone was adjusted mainly based on plasma 17OHP and T concentrations and, in more recently seen patients, based on the androstenedione and ACTH concentrations. The ACTH concentrations were used as a backup and interpreted according to the other results. Plasma T was not measured in the boys during the first 6 months of life or after the onset of puberty, because it is also produced by the testes. The criteria indicating good control were normal plasma renin activity for age, 17OHP below 15 nmol/liter, T below 0.7 nmol/liter, and normal androstenedione and ACTH concentrations (<16 pmol/liter). Commercial immunoassays were used to measure 17OHP (OHP-CT, Cis Bio, Gif sur Yvette, France), total T (Testo-CT2, Cis Bio), androstenedione (Immunotech, Marseille, France), cortisol (CORT-CT2, Cis Bio), and ACTH (immunoradiometric assay, Immunotech).
The following parameters were analyzed at diagnosis and at 0.5, 1, 2, 3, 4, 5, 10, and 15 yr of age in the classical form: height, pubertal stage, hydrocortisone and 9-fludrocortisone doses, and plasma 17OHP, T, androstenedione, ACTH, and renin activity. These parameters were analyzed at diagnosis and at 10 and 15 yr of age in the nonclassical form.
Genetic analysis
The CYP21 genes of all patients were analyzed using peripheral blood samples, once signed informed consent had been given by the parents. Molecular studies were performed according to a cascade strategy. The CYP21 gene was amplified by PCR of two fragments overlapping the third exon so as to avoid amplifying the CYP21P pseudogene that has an 8-bp deletion. The first fragment extended from the 5' end of the CYP21 gene to the 3rd exon, and the second fragment extended from the 3rd to the 10th exons (primers and PCR conditions are described in Ref. 21). The PCR products were sequenced directly with a model 373A automatic sequencer (22). Almost all one strand of the entire gene was first sequenced using four primers. The most frequent mutations were therefore screened (IVS2–13A/C
G, I172N, cluster of three mutations in exon 6: V281L, Q318X, and R356W). Then more rare mutations in exons 1 and 10 (mutations of the promoter, P30L, P453S, and mutations at codon 493) were checked. Lastly, very rare or new mutations were checked. The search for the 8-bp deletion in the third exon required amplification of another fragment with one specific primer in intron 2 and the other in exon 6. Thus, the entire gene was explored, including the coding regions, introns, and the 5' regulatory region, until the two mutations had been identified. Two large lesions may be missed if the CYP21 gene is not specifically amplified. CYP21 and CYP21P were amplified nonselectively, followed by Southern blotting studies (23) to demonstrate such lesions. Mutations identified in patients were assigned by familial studies when the parents were available. The appropriate enzyme was used for mutations that modified the restriction enzyme site, and other mutations were screened by sequencing.
Data are the mean ± SEM. Data for groups were compared by Wilcoxon ranking tests. Correlations were assessed by the Spearman correlation test.
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Results |
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The patients were divided into 5 genotype groups according to the predicted severity of the mutations (Table 1
). The 12 patients in group 0 (17.6%) were homozygous or compound heterozygous for a null mutation. The 23 patients in group A (33.8%) were homozygous for the IVS2 splice mutation or compound heterozygous for IVS2 and null mutations. All patients in these groups had the SW form. The 10 patients in group B (14.7%) were homozygous or compound heterozygous for the I172N mutation. They had a mixed distribution of phenotypes (5 with SW and 5 with SV). Two siblings with the same genotype (homozygous I172N) had different phenotypes; the brother (case 39) had SW, and the sister (case 40) had SV (normal plasma renin activity from diagnosis to 16 yr of age). The 18 patients in group C (26.5%) were homozygous or compound heterozygous for the V281L, and case 54 was homozygous or compound heterozygous for P30L mutations. All patients in this group had the nonclassical form. Group D contained 5 patients (7.4%).
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Groups 0, A, and B with the classical form
These were the 45 patients in groups 0, A, and B, of whom 40 had the SW (26 females and 14 males) form and 5 had the SV (3 females and 2 males) form (Table 1
). The patients with the SW form were found to have CAH because of ambiguous genitalia (20 females), weight loss due to the SW syndrome (5 females and 6 males), neonatal screening (1 female and 5 males), or prenatal diagnosis for the familial form (2 males). One patient (case 28) presented with hypospadias associated with primary tubular deficiency, which was probably not linked to CAH. The patients with the SV form were found to have CAH because of ambiguous genitalia (one female), premature pubarche (1 female and 2 males), or major acnea and the absence of breast development at 13 yr associated with the early attainment of adult height (one female). All females had virilization of the genitalia, with Prader stage II in 4 cases, III in 9 cases, IV in 14 cases, and V in 2 cases. The ages at diagnosis of the group 0, A, and B patients not diagnosed prenatally were 12.4 d in SW, 5.4 yr in males with SV (n = 2), and 5.8 yr in females with SV (n = 3).
Almost all (14 of 16) patients who underwent neonatal screening had very high 17OHP concentrations (mean, 208 pg/spot for a cut-off at 60 pg/spot), but 2 had 39 and 63 pg/spot at 3 d of age. These 2 patients (cases 38 and 43) belonged to group B. The initial plasma concentrations of 17OHP, measured after the first day of life, were between 70 and 2723 nmol/liter. Two females had normal concentrations on the first day of life (7.3 nmol/liter in case 17 and 30 nmol/liter in case 18). The females had elevated plasma T concentrations, above 2.5 nmol/liter in all cases (mean, 17.7 ± 0.7 nmol/liter). There was a significant positive correlation between the age at diagnosis and the 17OHP plasma concentration (n = 38; P = 0.003) and between the plasma 17OHP and T concentrations (n = 22; P = 0.03). SW resulted in a plasma sodium level less than 132 mEq/liter in 19 of 22 cases, plasma potassium above 6 mEq/liter in 19 of 22 cases, and plasma calcium above 2.8 mEq/liter in the 7 of 12 cases for whom information was available. All patients with SW had elevated plasma renin activity, but the initial concentrations were normal in 7 cases evaluated at the age of 1–13 d.
The patients with the classical form diagnosed before 60 d of age were separated into 2 groups for analysis of the impact of improved medical follow-up with time on height evolution. Nine older patients (7 females and 2 males) followed by us from birth had reached their final height, whereas the 19 younger patients (11 females and 8 males) were followed until they were 5 yr old because they were first seen more recently. The height SDS of the older patients were –0.5 ± 0.3 at 0.5 yr, 0.1 ± 0.3 at 1 yr, -0.7 ± 0.5 at 2 yr, 0.4 ± 0.4 at 5 yr, 0.3 ± 0.6 at 10 yr, and -0.9 ± 0.6 at 15 yr; the final height was –1.9 ± 0.3 SDS. The height SDS of the younger patients were 0.1 ± 0.3 at 0.5 yr, 0.3 ± 0.3 at 1 yr, -0.02 ± 0.2 at 2 yr, and 0.4 ± 0.4 at 5 yr. These values were not different from the target height or from those of older patients (Fig. 1). The older patients were given more hydrocortisone at 5 yr of age (P < 0.05), and less 9-fludrocortisone initially and at 0.5, 1, and 2 yr of age (P < 0.05) than were the younger patients. There was a positive correlation between the mean hydrocortisone dose given to older patients between 1 and 10 yr and the difference between the final and target heights (P < 0.05); those given the higher doses showed the greater difference between their final and target heights.
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The 10 females and 8 males in group C (Table 1) were found to have CAH because of premature pubarche (15 cases), pubertal delay (case 63), or familial genetic analysis (cases 46 and 49). One male who was homozygous for the V281L mutation (case 57) also had an optic glioma and neurofibromatosis 1. Four patients (cases 47, 54, 59, and 60) had partial glucocorticoid deficiency (poor cortisol response to ACTH simulation and/or increased basal plasma ACTH concentrations). The plasma renin activity was normal in all patients. Case 46, diagnosed by familial genetic analysis, remained untreated at 9 yr, but the parents had been given a written prescription should she suffer from an intercurrent disease.
Group D
The 1 female and 4 males in group D (Table 1) were found to have CAH because of premature pubarche. Three patients (cases 66–68) had partial glucocorticoid deficiency. Two siblings had the R341P mutation; the brother (case 65) had pubic hair at 5.1 yr and advanced bone age (12.5 yr), whereas the sister (case 64) had pubic hair at 1.7 yr without clitoromegaly. One patient (case 66) had an I172N mutation on one allele and a novel missense mutation E320L in exon 8, resulting in unknown enzyme activity on the other allele. He had pubic hair at 5 yr, advanced bone age (10 yr), and an elevated plasma ACTH concentration (181 pmol/liter). Another patient (case 67) had a recently described mutation (12) in which the 5'-end of CYP21 is replaced by the corresponding sequence of the CYP21P pseudogene. He had pubic hair at 5.4 yr, advanced bone age (10.5 yr), and high basal 17OHP concentration. A fifth patient (case 68) was homozygous or hemizygous for two mutations, P30L and H62L; he had pubic hair at 6.3 yr and advanced bone age (13 yr).
Comparison of the groups
Group 0 and A patients were younger at diagnosis (P < 0.02) and had higher 17OHP concentrations at the neonatal screening (P < 0.05) than the group B patients. The virilization of external genitalia was Prader stage IV or V in 16 of 23 females in groups 0 and A, whereas it was stage II or III in all 6 females in group B. Basal plasma 17OHP was higher in group 0 than in groups A and B at diagnosis, but plasma T and androstenedione were similar. There were no differences among the 3 groups for evolution of height, hydrocortisone, and 9-fludrocortisone doses during the first 5 yr of life (Fig. 2).
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Comparison of groups C and D showed significant differences in the age at premature pubarche (6.9 ± 0.1 in group C and 4.2 ± 0.3 yr in group D; P < 0.01); age at diagnosis (P < 0.03); bone age advance (2.0 ± 0.1 and 5.5 ± 0.3 yr; P < 0.01); basal plasma 17OHP (P < 0.01), cortisol (P < 0.03), T (P < 0.02), and androstenedione (P < 0.03) concentrations; and hydrocortisone dose (20.3 ± 0.7 mg/m2/d in group D; P < 0.05) 1 yr after the onset of the treatment and at 10 yr of age (19.6 ± 1 mg/m2/d; P < 0.03). The height (groups C and D) was 2.5 ± 0.4 SDS at diagnosis (mean age, 6.9 ± 0.8 yr), 1.8 ± 0.3 SDS after 1 yr of treatment, and 1.2 ± 0.3 SDS at 10 yr of age; the final heights were similar.
The final heights were similar in classical (n = 16; –2 ± 0.2 SDS) and nonclassical (n = 11; –1.2 ± 0.4 SDS) forms (P = 0.057; Table 2). They were below target heights (P < 0.02 and 0.03, respectively).
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Severe complications occurred 14 times in 11 patients (Table 3). They were often due to acute disease, particularly gastrointestinal disease. Hypoglycemia, suggesting severe glucocorticoid deficiency, occurred 9 times between the ages of 1 and 3 yr and caused the death of 2 patients. The hydrocortisone dose of these patients was not significantly different from that of subjects of the same age without complications. It was during this period of childhood that the hydrocortisone dose was lowest. Three patients suffered a salt loss crisis with hyponatremia between the ages of 2.5 and 5 yr. The frequency of these accidents was similar in all groups (2 in group 0, 8 in group A, and 1 in group B). No acute severe complication occurred in groups C and D.
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Discussion |
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A good correlation was found between the severity of the genetic defects and the clinical-laboratory features. All patients with severe mutations (groups 0 and A) had the SW form, whereas all patients in group C had the nonclassical form. However, the phenotype of the group B patients varied, and the phenotype differed even between siblings within the same family. Others have reported a wide spectrum of phenotypes with the I172N mutation, including SW, SV, and nonclassical forms, with the frequency of SW forms being between 25–65% (8, 10, 11, 12, 24). The results of the molecular study confirmed that the intron 2 splice site mutation is the most prevalent in the classical form (8, 9, 24, 25, 26), whereas the V281L mutation is the most prevalent in the nonclassical form (12). Another group (D) contained patients carrying mutations, but their enzyme activity was not investigated by in vitro expression. This group seemed to be different from the others. There was no salt wasting, the onset of pubic hair development was earlier than in the group C patients, bone age advance was greater, the plasma concentrations of 17OHP and T at diagnosis were higher, there was partial cortisol deficiency, and they needed higher doses of hydrocortisone. The single female in group D had one mutation (R341P) that produced a clinical picture different from the SV form, as there was no virilization at birth. This mutation, changing an arginine to a proline, was located in an arginine-rich domain (338–361 bp) involved in redox partner interaction (27). This change of arginine to proline should also modify the tertiary structure of P450c21. One male was homozygous for one mutation recently described by Deneux et al. (12), in which a large gene conversion replaced the 5' end of CYP21 with the corresponding sequence of the CYP21P pseudogene. The patient reported by these researchers was a women with the nonclassical form and extremely high basal 17OHP (203 nmol/liter), T, and androstenedione concentrations. The data suggest that the enzyme activity is intermediate between those of the classical (<3%) and nonclassical (30–50%) forms. L’Allemand et al. (21) reported a girl with a special genotype (compound heterozygous for two different 30-kb deletions) whose phenotype suggested that she also had an intermediate form. The two other novel mutations that we report, E320L and H62L, affected males, so we cannot differentiate between the SV and nonclassical forms.
The distribution of Prader genital stages seems to be similar to that reported by others (11, 28). Two of the groups with severe mutations (groups 0 and A) had similar characteristics. They were diagnosed neonatally and had similar degrees of virilization and androgen concentrations at diagnosis. The patients in these two groups showed the same evolution of height, and hydrocortisone and 9-fludrocortisone doses. This is explained by the fact that enzyme activity was very low in both (0 for group 0; 0–1% for group A). The group B patients were older at diagnosis (up to 13 yr), and none of the females showed Prader IV or V virilization. Although their plasma T and androstenedione concentrations were not different at diagnosis, the plasma 17OHP concentrations at neonatal screening during the first week of life were lower than those in groups 0 and A. A lower androgen concentration during fetal life could explain the less severe virilization. However, the hydrocortisone doses given to these three groups were similar, at least until 5 yr of age. This suggests that similar hydrocortisone doses are necessary to suppress adrenal androgen hypersecretion. Half the children in group B had the SW form, and their doses of 9-fludrocortisone were not different from those given to groups 0 and A. None of them had a salt crisis outside the neonatal period, and the dose of 9-fludrocortisone could possibly have been reduced, as suggested by the decrease in dose with age, particularly after 5 yr. However, these patients must be given mineralocorticoid to normalize their plasma renin activity. The control of elevated plasma renin activity enables the glucocorticoid dose to be reduced by correcting the hypovolemia that stimulates ACTH production (1). Height evolutions during the first 5 yr were similar in these three groups. The group C patients have approximately 30–50% enzyme activity. Their plasma 17OHP, androstenedione, and T concentrations at diagnosis were lower than those in groups 0, A, and B. The hydrocortisone dose per unit body area was stable during puberty. In contrast, the dose of hydrocortisone given to patients with the classical forms must be increased during puberty. The pattern of the hydrocortisone dose given to group D patients was similar to that given to patients with the classical form, particularly the increase needed during puberty. Charmandari et al. (29) suggest that puberty is associated with alterations in cortisol pharmacokinetics, resulting in increased clearance and volume of distribution, with no change in half-life.
Final height was slightly, but not significantly (P = 0.057), lower in the classical than in the nonclassical form. Only 16 of the patients with the classical form, among them the 9 followed by us from birth, had reached their final height; it was lower than the target height by 1.6 SDS. These values are similar to published ones (30, 31, 32, 33). A meta-analysis published by Eugster et al. (30) gave the mean final height of 561 patients as –1.4 SDS, lower than the target height by 1.2 SDS in the 204 patients for whom target heights were available. The females in our study began puberty at a normal age; menarche occurred 2 yr after the onset of puberty, but pubertal growth was lower than normal (12.6 vs. 25 cm). Others have reported reduced pubertal growth in boys and girls (31, 32). This reduced pubertal growth can be due to a moderate bone age advance at the onset of puberty, the high dose of glucocorticoid, and possibly bone lesions caused by overtreatment during the 3 first yr of life. As the medical follow-up of patients has improved with time (neonatal screening and plasma measurements), patients who reached their final height were compared with patients first seen more recently. There was no difference in the growth patterns of these 2 groups during the first 5 yr. Charmandari et al. (34) showed that the 17OHP concentrations of patients with the classical form treated with hydrocortisone have circadian variations, with peak values between 4–9 h. They suggested giving the highest dose of hydrocortisone in the morning when the hypothalamic-pituitary-adrenal axis was the most active. They also demonstrated that the mean plasma 8 h androstenedione level was strongly correlated with the integrated 17OHP concentrations, and so should be a good marker of adrenal suppression. The final height and pubertal growth of our 11 patients with the nonclassical form were also reduced despite the lower glucocorticoid dose (35). This problem of final short stature led to new treatment approaches under investigation in classical forms: combination therapy with a reduced hydrocortisone dose, GH and GnRH agonist, antiandrogen, and aromatase inhibitor or bilateral adrenalectomy in the most affected patients (36, 37, 38).
Complications were frequent and severe despite hormone replacement and parental education. These complications were mainly hypoglycemia due to glucocorticoid deficiency; salt loss crises were rare. Jääskeläinen et al. (39) and Donaldson et al. (40) reported that 4.6% of patients with the classical form died, and 9% suffered from hypoglycemia, similar to our finding of 4.4% deaths and 7.7% cases of hypoglycemia. The hypoglycemia occurred between the ages of 1 and 3 yr, when the hydrocortisone doses were lowest. These patients had normal plasma androgen concentrations a few weeks or months before the occurrence of complications. We therefore suggest that the dose of glucocorticoid should be kept above 12 mg/m2/d for patients with the classical form. It is important to educate the parents, particularly as we insist on giving injectable forms as soon as any gastrointestinal symptoms begin, before the patient is taken to hospital (41, 42).
In conclusion, both neonatal screening and genotyping can help in the management of CAH (43). This is particularly true for patients with severe mutations (groups 0 and A) and those with the SW form. Genotyping is also very helpful for genetic counseling, particularly for siblings (44, 45). Above all, early diagnosis prevents life-threatening events such as hypoglycemia and salt loss. Early diagnosis, optimal medical and surgical treatment, and attention to compliance (44) will help to preserve fertility and psychosocial well-being.
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Footnotes |
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Abbreviations: CAH, Congenital adrenal hyperplasia; 17OHP, 17-hydroxyprogesterone; SDS, SD score; SV, simple virilizing; SW, salt wasting; T, testosterone.
Received September 11, 2002.
Accepted March 10, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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K. Lin-Su, M. G. Vogiatzi, I. Marshall, M. D. Harbison, M. C. Macapagal, B. Betensky, S. Tansil, and M. I. New Treatment with Growth Hormone and Luteinizing Hormone Releasing Hormone Analog Improves Final Adult Height in Children with Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3318 - 3325. [Abstract] [Full Text] [PDF]
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