Marie-Charles Raux-Demay

Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency

OBJECTIVE It remains controversial whether long-term glucocorticoids are charged of bone demineralization in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The aim of this study was to know whether cumulative glucocorticoid dose from the diagnosis in childhood to adulthood in patients with CAH had a negative impact on bone mineral density (BMD). DESIGN This was a retrospective study. METHODS Thirty-eight adult patients with classical and non-classical CAH were included. BMD was measured in the lumbar spine and femoral neck. Total cumulative glucocorticoid (TCG) and total average glucocorticoid (TAG) doses were calculated from pediatric and adult files. RESULTS We showed a difference between final and target heights (-0.82+/-0.92 s.d. for women and -1.31+/-0.84 s.d. for men; P<0.001). Seventeen patients (44.7%) had bone demineralization (35.7% of women and 70% of men). The 28 women had higher BMD than the 10 men for lumbar (-0.26+/-1.20 vs -1.25+/-1.33 s.d.; P=0.02) and femoral T-scores (0.21+/-1.30 s.d. versus -1.08+/-1.10 s.d.; P=0.007). In the salt-wasting group, women were almost significantly endowed with a better BMD than men (P=0.053). We found negative effects of TCG, TAG on lumbar (P<0.001, P=0.002) and femoral T-scores (P=0.006, P<0.001), predominantly during puberty. BMI was protective on BMD (P=0.006). CONCLUSION The TCG is an important factor especially during puberty for a bone demineralization in patients with 21-hydroxylase deficiency. The glucocorticoid treatment should be adapted particularly at this life period and preventive measures should be discussed in order to limit this effect.

Clinical Description of Infants with Congenital Hypothyroidism and Iodide Organification Defects

Aims: To describe the phenotype of a large group of children with congenital hypothyroidism (CH) and iodide organification defect (IOD), suspected based on normal thyroid position and abnormal perchlorate discharge test, as first step of a project evaluating correlations between phenotypes and genotypes. Methods: 71 children born in Paris between 1980 and 2006 were included. Two groups were defined according to perchlorate discharge: total IOD (TIOD) when the release was above 90% and partial IOD (PIOD) between 10 and 90%. Comparisons between groups were performed using SPSS 14.0 for Windows. Results: The incidence of IOD over the 2003–2006 period was 1:20,660. Of the 71 children, 61 had PIOD and 10 TIOD. Compared to PIOD, TIOD was characterized by greater clinical severity. A wide spectrum of clinical features was seen in the PIOD group. Evolution showed transient hypothyroidism in 10/61 patients with PIOD and 1/10 TIOD patients. Conclusions: Severe presentation in the majority of TIOD patients suggests dysfunction of a key iodide-organification enzyme. In contrast, the variety of clinical features in PIOD group suggests that diverse mechanisms may lead to PIOD, such as delayed or reduced activity of enzymes involved in hormonogenesis or defects in iodine storage and release.

Insulin-Like Growth Factor-I Gene Analysis in Subjects with Constitutionally Variant Stature

ABSTRACT: The IGF-I gene from leukocyte DNA of a control population of normal stature was studied using Southern blotting. Restriction fragment lengths for 21 enzymes were determined and three restriction fragment length polymorphisms (RFLP) were found (EcoRV, HindIII, and PvuII). In addition, the IGF-I gene of 64 constitutionally short subjects, five Pygmies, and 10 constitutionally tall subjects was analyzed. No IGF-I gene alterations were detectable by Southern blot in any of these conditions. Linkage analysis using genetic markers (RFLP) yielded results that were uninformative for five constitutionally short families investigated, owing to the limited number of RFLP and their low incidence (17% for the 5.2- kb HindIII, 5-kb PvuII RFLP alleles, and 13% for the 13- kb EcoRV RFLP allele). The EcoRV RFLP was found to map near Exon 1. The incidence of the 13-kb polymorphic allele with EcoRV proved to be lower (4%) in the group with constitutionally short stature than in controls. These results could suggest that modifications in the region of the IGF-I gene may be involved in constitutionally short subjects.

Chapter 16 – Cushing's disease

Publisher Summary Cushings disease is the most frequent cause of spontaneous Cushings syndrome in adults. In most series its prevalence is approximately 70% with a definite female preponderance, the female/male ratio ranging between 3:1 and 10:1. In reference series of 809 adult patients with spontaneous Cushings syndromes, Cushings disease accounts for 68% of the cases, and the female/male ratio is 2.8. Distribution of the age at diagnosis shows a peak in adult females in the 25-45-year range. In children, the causes of Cushings syndrome have a different distribution. Primary adrenocortical tumors are more frequent and Cushings disease accounts for about 50% of the cases. Children with this condition are usually older than nine with an equal sex ratio. Cushings disease accounts for 50% of Cushings syndrome and is almost always caused by a pituitary microadenoma. Cushings syndrome refers to the manifestations of chronic glucocorticoid excess and may result from various causes. In Cushings disease pituitary adrenocorticotropic hormone (ACTH) over secretion induces bilateral adrenocortical hyperplasia and excess production of cortisol, adrenal androgens and 11-deoxycorticosterone, which together provoke the clinical and biologic features of the disease. Cushings disease is rare; its true incidence, which varies with age and sex, is difficult to evaluate.

SFRP-08 – Recherche clinique – Hypothyroïdie congénitale avec trouble de l’organification de l’iode : description phénotypique précise d’une cohorte d’enfants

L’hypothyroidie congenitale (HC) est l’une des maladies endocriniennes les plus frequentes chez l’enfant (1/3500). Si les athyreoses et les ectopies en representent la cause principale, les troubles de l’organification de l’iode (TOID) en sont une cause non negligeable (incidence inconnue). Leur physiopathologie reste mal elucidee et seuls quelques genes codant pour des facteurs cles de l’hormonosynthese (thyroperoxydase, DUOX2 oxidase, pendrin) ont ete incrimines sans qu’aucune correlation genotype- phenotype n’ait plus etre clairement etablie a ce jour. Le but de cette etude a donc ete de 1) determiner l’incidence des TOID. 2) decrire le phenotype precis d’une large cohorte de patients atteints, ceci afin ulterieurement de tenter une correlation genotype- phenotype apres etude moleculaire. Patients 71 enfants nes entre 1980 et 2006 atteints d’HC due a un TOID et suivis dans 3 hopitaux pediatriques parisiens ont ete retrospectivement inclus dans cette etude. Resultats Un TIOD a ete identifie chez 13.6 % des enfants atteints d’HC depistes dans la periode 2003-2006 (incidence 1 : 20.660). Parmi les 71 enfants porteurs d’un TIOD etudies, 61 avaient un TIOD partiel (defini par un taux de captage thyroidien a la scintigraphie, 1h apres administration de perchlorate entre 10 et 85 %) et 10 avaient un trouble total (taux > 90 %). Dans l’ensemble, les enfants porteurs d’un TIOD total presentaient une symptomatologie relativement uniforme et significativement plus severe que les patients avec TIOD partiel (hypotonie, ictere prolonge, distension abdominale, cri rauque) (p Conclusion La symptomatologie severe et uniforme des sujets atteints d’HC due un TIOD total suggere un defaut unique dans un facteur cle de l’hormonosynthese. Inversement, la presentation tres variable des enfants atteints d’HC due a un TIOD partiel suggere la responsabilite de plusieurs facteurs impliques dans l’organification de l’iode.

115 Detection of heterozygous carrier for 21-hydroxylase deficiency by plasma 21-deoxycortisol measurment

Plasma 21-deoxycortisol (21 DF) was measured by using an anti-serum raised in the rabbit with 21-deoxycortisol-3-0-carboxymethyl oxime-BSA. This anti-serum cross-reacted with 11-deoxycortisol (0.08%), corticosterone (0.35%), cortisol (0.6%) and 17-hydroxyprogesterone (1.6%). 21 DF was separated by celite partition chromatography and was eluted in the fraction isooctane 70v/ethylacetate 30v, together with 11-deoxycortisol and corticosterone. In 38 healthy volunteers (16 men and 22 women) 21 DF mean basal value was 166 pg/ml at 8 a.m. with a range of 66 - 401 pg/ml. After a Synacthen test, performed in 14 subjects, the maximum mean level was 414 pg/ml (151-930). In 31 congenital adrenal hyperplasia family members heterozygous for 21-hydroxylase deficiency proved by HLA genotyping, 21 DF mean basal level was 323 pg/ml (50-1,380). After Synacthen it increased up to 2,380 (1,070-9,060). In contrast with 17-hydroxyprogesterone which was also measured and which remained in the normal range after Synacthen in 12 cases out of the 31 , 21 DF under stimulation increased to pathological levels in all the cases studied. Therefore we believe that plasma 21 DF measurement could be of great interest in the biological detection of heterezygous subjects for 21-hydroxylase deficiency.

Fertility in Women With Late-Onset Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency. The majority of patients (n = 33) were seen for isolated postpubertal hirsutism, 9 patients consulted for sterility, and 11 for irregular menstrual cycles. At the time of diagnosis, the ages of patients ranged from 15-40 yr (mean +/- SD, 24.6 +/- 5.2). No patient had major signs of virilization. The plasma 17-hydroxyprogesterone level was higher than normal in all patients (26.8 +/- 18.9 nmol/L; range, 3.4-139.4) and dramatically increased to 140.1 +/- 80.6 nmol/L (range, 35.2-324.2) after ACTH treatment. Plasma androgen levels were high (testosterone, 3.25 +/- 2.03 nmol/L; delta 4-androstenedione, 13.65 +/- 5.60 nmol/L). Plasma basal and LHRH-stimulated values were normal for FSH and high for LH. Basal and TRH-stimulated plasma PRL levels were normal. Among these 53 LAH patients, only 20 desired a pregnancy. These had a total of 38 pregnancies. Ten patients became pregnant before the diagnosis of LAH and without any treatment; they had a total of 18 pregnancies, 12 of which were successful. Moreover, 19 normal pregnancies without any spontaneous abortion were carried to term by 14 of 16 hydrocortisone-treated patients. One patient needed the association of one cure of clomiphene citrate. Hypofertility in LAH patients seems, therefore, to be relative. Its mechanism is hormonal, with anovulation or dysovulation, due to the continuous steroid feedback of adrenal origin on the hypothalamo-pituitary axis. Hydrocortisone is the appropriate treatment in most cases, reducing adrenal androgen overproduction and relieving hypothalamic-pituitary gonadotropin function, thereby making possible cyclic ovarian activity and ovulations.

Cyproterone Acetate versus Hydrocortisone Treatment in Late-Onset Adrenal Hyperplasia

Thirty late-onset adrenal hyperplasia patients consulting for isolated hirsutism were randomly divided into two groups; group 1 (n = 16) was treated with hydrocortisone in order to suppress androgen adrenal secretion, and group 2 (n = 14) received cyproterone acetate (CPA) antiandrogen therapy to inhibit peripheral androgen activity. The clinical and hormonal effects of each type of treatment were evaluated. Before treatment, the clinical and hormonal profiles of the two patient groups did not differ significantly. Excellent clinical evolution in terms of the regression of hirsutism was observed in the CPA-treated patients (54% decrease in the clinical score in 1 yr), in contrast with the slight decrease in hirsutism (26%) after hydrocortisone treatment. In hydrocortisone-treated patients, plasma androgen decreased to normal levels: testosterone from 3.05 +/- 1.45 to 1.46 +/- 0.42 nmol/L and delta 4-androstenedione from 13.6 +/- 4.1 to 6.33 +/- 1.47 nmol/L. Conversely, in CPA-treated patients, only a slight decrease in testosterone from 2.98 +/- 1.98 to 2.29 +/- 0.64 nmol/L and in delta 4-androstenedione from 12.9 +/- 5.9 to 9.86 +/- 2.23 nmol/L was observed. This slight decrease in plasma androgens contrasts with the rapid clinical improvement after CPA. These results emphasize the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. Moreover, they indicate that peripheral antiandrogen therapy may be more appropriate in late-onset adrenal hyperplasia patients than conventional adrenal inhibition using cortisone therapy.

CONGENITAL VIRILIZING ADRENAL HYPERPLASIA (CVAH) DUE TO 21 HYDROXYLASE DEFICIENCY, RESULTS OF THERAPY WITH CYPROTERONE ACETATE (CA)

Results obtained from ten prepubertal patients (6 girls, 4 boys) suffering of CVAH were compared over 12-41 months periods before and over 14-52 months periods during CA therapy (63 ± 21 (SD)mg/m2/day). At the beginning of treatment with CA, growth parameters were as follow : chronological (Ch) ages 5 to 10 years, heights (H) 102.5 ± 9.2% of normal H for Ch ages, bone (B) ages 6 to 92 (mean 49) months over Ch ages. CA induced decreases in growth velocity (6.9 ± .66 (SEN) to 4.3 ± .54 cm/year, p < .01), in bone maturation (2.4 ± .76 to .35 ± .11 years/Ch year p < .05) and in B/H ages ratios (1.42 ± .09 to 1.23 ± .06, p < .05). In spite of reduced cortisol therapy from 15.4 ± 1.23, before, to 12.24 ± .72 mg/m2/day, during CA treatment, (p < .05), 17 hydroxyprogesterone (17OHP) and testosterone (T) plasma levels decreased from 62 ± 9.8 to 22.7 ± 7 (p < .01) and from .42 ± .07 to .17 ± .03 (p < .05) respectively. When compared to normal values for B ages, most plasma DHA values were normal before (9/10) and during (7/10), most Δ4 androstenedione (Δ4A) values were elevated before (9/10) and normal (9/10) during CA treatment, while Δ4A/T ratios increased significantly from 3.7 ± .32 to 6.4 ± .86 (p < .01). In conclusion, CA appears to be of interest in the treatment of prepubertal patients with CVAH. The antiandrogenic effect is demonstrated by the improvement of bone maturation, the inhibition of ACTH production by the decreases in 17OHP levels. In addition there is evidence of a decrease in the conversion rates of adrenal androgens to testosterone.

125 Plasma consuntration of androgens, cortisol and its precursors in virilizing adrenal tumors in children

Five children (3 girls and 2 boys) aged 1 to 3 years were investigated. Virilization was isolated in 2 (group A), associated with Cushings syndrome in 2 (group B) and with feminization in 1 (group C). The individual patterns of androgens were variable. However, in 4 out of 5 cases, the relative rises above normal levels (N) were greater for androstenedione (Δ4) 4 to 100 times, than for dehydroepiandrosterone (DHA) 1.4 to 25 times. 11 β-OH-androstenedione (11 β-OH-Δ4) measured in groups B and C, was found low normal in C (0.9 ng/ml) and high in B (2.8 and > 10 ng/ml) (N : 0.9 - 2 ng/ml). 17-OH-Progesterone was elevated in group B : 3.5 and 4.7 ng/ml and normal in groups B and C (N : 0.2 - 0.9 ng/ml). Only one of B patients showed a high cortisol level (255 ng/ml) 11-deoxycortisol levels were increased in all groups A, B and C.Conclusions: a) androstenedione is the androgen the most prominently elevatedb) the rise in 11-déoxycortisol is a common featurec) 11 β-OH-androstenedione may be low in spite of high levels of Δ4d) a possible mild block on 11 β-hydroxylation could be suspected in these tumors