Publications by authors named "Gabriela Guercio"

25 Publications

  • Page 1 of 1

Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 () gene.

Proc Natl Acad Sci U S A 2020 06 3;117(24):13680-13688. Epub 2020 Jun 3.

Human Developmental Genetics Unit, Institut Pasteur, 75724 Paris, France;

Sex determination in mammals is governed by antagonistic interactions of two genetic pathways, imbalance in which may lead to disorders/differences of sex development (DSD) in human. Among 46,XX individuals with testicular DSD (TDSD) or ovotesticular DSD (OTDSD), testicular tissue is present in the gonad. Although the testis-determining gene is present in many cases, the etiology is unknown in most -negative patients. We performed exome sequencing on 78 individuals with 46,XX TDSD/OTDSD of unknown genetic etiology and identified seven (8.97%) with heterozygous variants affecting the fourth zinc finger (ZF4) of Wilms' tumor 1 (WT1) (p.Ser478Thrfs*17, p.Pro481Leufs*15, p.Lys491Glu, p.Arg495Gln [x3], p.Arg495Gly). The variants were de novo in six families ( = 4.4 × 10), and the incidence of WT1 variants in 46,XX DSD is enriched compared to control populations ( < 1.8 × 10). The introduction of ZF4 mutants into a human granulosa cell line resulted in up-regulation of endogenous Sertoli cell transcripts and XX mice display masculinization of the fetal gonads. The phenotype could be explained by the ability of the mutated proteins to physically interact with and sequester a key pro-ovary factor β-CATENIN, which may lead to up-regulation of testis-specific pathway. Our data show that unlike previous association of WT1 and 46,XY DSD, ZF4 variants of WT1 are a relatively common cause of 46,XX TDSD/OTDSD. This expands the spectrum of phenotypes associated with WT1 variants and shows that the WT1 protein affecting ZF4 can function as a protestis factor in an XX chromosomal context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1921676117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306989PMC
June 2020

Estrogens in Human Male Gonadotropin Secretion and Testicular Physiology From Infancy to Late Puberty.

Front Endocrinol (Lausanne) 2020 25;11:72. Epub 2020 Feb 25.

Endocrinology Department, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan", Buenos Aires, Argentina.

Several reports in humans as well as transgenic mouse models have shown that estrogens play an important role in male reproduction and fertility. Estrogen receptor alpha (ERα) and beta (ERβ) are expressed in different male tissues including the brain. The estradiol-binding protein GPER1 also mediates estrogen action in target tissues. In human testes a minimal ERα expression during prepuberty along with a marked pubertal up-regulation in germ cells has been reported. ERβ expression was detected mostly in spermatogonia, primary spermatocytes, and immature spermatids. In Sertoli cells ERβ expression increases with age. The aromatase enzyme (cP450arom), which converts androgens to estrogens, is widely expressed in human tissues (including gonads and hypothalamus), even during fetal life, suggesting that estrogens are also involved in human fetal physiology. Moreover, cP450arom is expressed in the early postnatal testicular Leydig cells and spermatogonia. Even though the aromatase complex is required for estrogen synthesis, its biological relevance is also related to the regulation of the balance between androgens and estrogens in different tissues. Knockout mouse models of aromatase (ArKO) and estrogen receptors (ERKOα, ERKOβ, and ERKOαβ) provide an important tool to study the effects of estrogens on the male reproductive physiology including the gonadal axis. High basal serum FSH levels were reported in adult aromatase-deficient men, suggesting that estrogens are involved in the negative regulatory gonadotropin feedback. However, normal serum gonadotropin levels were observed in an aromatase-deficient boy, suggesting a maturational pattern role of estrogen in the regulation of gonadotropin secretion. Nevertheless, the role of estrogens in primate testis development and function is controversial and poorly understood. This review addresses the role of estrogens in gonadotropin secretion and testicular physiology in male humans especially during childhood and puberty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2020.00072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051936PMC
March 2021

Androgen Insensitivity Syndrome: Clinical Phenotype and Molecular Analysis in a Single Tertiary Center Cohort

J Clin Res Pediatr Endocrinol 2019 02 25;11(1):24-33. Epub 2018 Sep 25.

Hospital de Pediatria Garrahan, Endocrinology Service, Buenos Aires, Argentina

Objective: The aim of this study was the molecular characterization of the gene as the cause of 46,XY disorder in our population.

Methods: We studied 41, non related, 46,XY disorder of sexual differentiation index cases, having characteristics consistent with androgen insensivity syndrome (AIS). Genomic DNA was isolated from peripheral blood leukocytes of all patients and 25 family members from 17 non-related families.

Results: The gene analysis revealed an abnormal sequence in 58.5% of the index patients. All of the complete AIS (CAIS) cases were genetically confirmed, while in the partial form (PAIS) a mutation in was detected in only 13 (43.3%). Molecular studies revealed other affected or carrier relatives in 87% of the index cases. The mutations were found spread along the whole coding sequence, with a higher prevalence in the ligand binding domain. Nine out of 23 (39%) mutations were novel. In 17% of patients with detected mutations, somatic mosaicism was detected in leucocyte DNA. In our cohort, long-term follow up gender dysphoria, raised as male or female, was not found. Finally, in suspected PAIS, the identification of mutation occurred significantly less than in CAIS patients.

Conclusion: Improved knowledge of the components of the complex and signaling network might contribute to long term outcome and genetic counseling in AIS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4274/jcrpe.galenos.2018.2018.0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398199PMC
February 2019

Accelerated Pubertal Tempo in a 46,XY Aromatase-Deficient Patient.

Horm Res Paediatr 2018 31;90(4):275-282. Epub 2018 Aug 31.

Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina.

Background: Aromatase deficiency is a rare autosomal recessive disorder. 46,XY-affected patients often remain undiagnosed until late puberty. Only 2 pediatric cases have been reported. Data on pubertal development in affected males are scarce.

Aim: To report the clinical phenotype and hormonal studies of an aromatase-deficient boy during the prepubertal and early pubertal period.

Results: The patient was the older brother of a 46,XX girl with aromatase deficiency. Molecular analysis revealed a previously reported homozygous mutation (Arg192Cys) in the CYP19A1 gene. Pubertal onset was at 9.8 years. At 11.3 years of age, signs of rapidly progressive puberty were seen. Laboratory tests revealed normal pubertal basal and GnRH-stimulated gonadotropin levels, normal Sertoli cell markers, and increased testosterone. The prepubertal lumbar spine bone mineral density (BMD) was normal but pubertal bone mineral accrual was incomplete, leading to osteopenia.

Conclusion: Estrogen restraint on gonadotropin secretion has been demonstrated in animal and human models. Interestingly, our patient presented with accelerated puberty and apparently normal pituitary gonadal function. These findings suggest that aromatase activity may be required to define pubertal progression in boys. Estrogen deficiency due to aromatase deficiency is responsible for insufficient bone mineral accrual during puberty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000492128DOI Listing
April 2019

Mutation of HSD3B2 Gene and Fate of Dehydroepiandrosterone.

Vitam Horm 2018 30;108:75-123. Epub 2018 Jun 30.

Endocrine Department, Hospital de Pediatría Garrahan, Buenos Aires, Argentina; National Scientific and Technical Research Council, Buenos Aires, Argentina. Electronic address:

3βHSD2 enzyme is crucial for adrenal and gonad steroid biosynthesis. In enzyme deficiency states, due to recessive loss-of-function HSD3B2 mutations, steroid flux is altered and clinical manifestations result. Deficiency of 3βHSD2 activity in the adrenals precludes normal aldosterone and cortisol synthesis and the alternative backdoor and 11-oxygenated C19 steroid pathways and the flooding of cortisol precursors along the Δ5 pathway with a marked rise in DHEA and DHEAS production. In gonads, it precludes normal T and estrogen synthesis. Here, we review androgen-dependent male differentiation of the external genitalia in humans and link this to female development and steroidogenesis in the developing adrenal cortex. The molecular mechanisms governing postnatal adrenal cortex zonation and ZR development were also revised. This chapter will review relevant clinical, hormonal, and genetic aspects of 3βHSD2 deficiency with emphasis on the significance of alternate fates encountered by steroid hormone precursors in the adrenal gland and gonads. Our current knowledge of the process of steroidogenesis and steroid action is derived from pathological conditions. In humans the 3βHSD2 deficiency represents a model of nature that reinforces our knowledge about the role of the steroidogenic alternative pathway in sex differentiation in both sexes. However, the physiological role of the high serum DHEAS levels in fetal life as well as after adrenarche remains to be elucidated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.vh.2018.05.002DOI Listing
November 2018

Androgen Insensitivity Syndrome at Prepuberty: Marked Loss of Spermatogonial Cells at Early Childhood and Presence of Gonocytes up to Puberty.

Sex Dev 2017 24;11(5-6):225-237. Epub 2018 Jan 24.

Servicio de Endocrinología, Hospital de Pediatría 'Prof. Dr. Juan Pedro Garrahan', Buenos Aires, Argentina.

Androgen insensitivity syndrome (AIS) is a hereditary condition in patients with a 46,XY karyotype in which loss-of-function mutations of the androgen receptor (AR) gene are responsible for defects in virilization. The aim of this study was to investigate the consequences of the lack of AR activity on germ cell survival and the degree of testicular development reached by these patients by analyzing gonadal tissue from patients with AIS prior to Sertoli cell maturation at puberty. Twenty-three gonads from 13 patients with AIS were assessed and compared to 18 testes from 17 subjects without endocrine disorders. The study of the gonadal structure using conventional microscopy and the ultrastructural characteristics of remnant germ cells using electron microscopy, combined with the immunohistochemical analysis of specific germ cell markers (MAGE-A4 for premeiotic germ cells and of OCT3/4 for gonocytes), enabled us to carry out a thorough investigation of germ cell life in an androgen-insensitive microenvironment throughout prepuberty until young adulthood. Here, we show that germ cell degeneration starts very early, with a marked decrease in number after only 2 years of life, and we demonstrate the permanence of gonocytes in AIS testis samples until puberty, describing 2 different populations. Additionally, our results provide further evidence for the importance of AR signaling in peritubular myoid cells during prepuberty to maintain Sertoli and spermatogonial cell health and survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000486089DOI Listing
October 2018

Fertility Issues in Disorders of Sex Development.

Endocrinol Metab Clin North Am 2015 Dec 3;44(4):867-81. Epub 2015 Sep 3.

CONICET - FEI - División de Endocrinología, Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), Hospital de Niños Ricardo Gutiérrez, Gallo 1330, Buenos Aires C1425EFD, Argentina; Departamento de Histología, Biología Celular, Embriología y Genética, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires C1121ABG, Argentina. Electronic address:

Fertility potential should be considered by the multidisciplinary team when addressing gender assignment, surgical management, and patient and family counselling of individuals with disorders of sex development. In 46,XY individuals, defects of gonadal differentiation or androgen or anti-Müllerian hormone synthesis or action result in incomplete or absent masculinization. In severe forms, raised as females, motherhood is possible with oocyte donation if Müllerian ducts have developed. In milder forms, raised as males, azoospermia or oligospermia are frequently found, however paternity has been reported. Most 46,XX patients with normal ovarian organogenesis are raised as females, and fertility might be possible after treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ecl.2015.07.012DOI Listing
December 2015

Five new cases of 46,XX aromatase deficiency: clinical follow-up from birth to puberty, a novel mutation, and a founder effect.

J Clin Endocrinol Metab 2015 Feb 21;100(2):E301-7. Epub 2014 Nov 21.

Endocrinology Service (R.M., N.P.G., M.Co., G.G., M.J., P.R., D.M.W., M.Ci., M.A.R., A.B., N.S.), Laboratory of Cellular Biology and Retrovirus (C.R.), Hospital de Pediatria Garrahan, C1245AAM Buenos Aires, Argentina; Endocrine Service (G.P.), Hospital Infantil Municipal de Córdoba, 5000 Córdoba, Argentina; Endocrine Service (J.G.F.), Hospital Regional de Concepcion, CPT4146GXD Tucuman, Argentina; and Endocrine Service (M.M.), Hospital de Niños de la Santísima Trinidad de Córdoba, 5000 Córdoba, Argentina.

Context: Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with aromatase deficiency have been described in both sexes.

Objective: The objective of the study was to detect CYP19A1 mutations in five aromatase-deficient 46,XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients.

Design: The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed.

Patients: Clinical and biochemical findings in five new cases and one previously reported female aromatase-deficient patient (46,XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency as well as other steroidogenic defects were ruled out.

Results: Phenotypic variability among the affected patients was found during follow-up. Direct sequencing of the CYP19A1 gene from genomic DNA revealed one novel mutation (c.574C>T) in two patients. In silico analysis predicted the c.574C>T mutation to be probably damaging. Four of six nonrelated patients presented with the c.628G>A splice mutation. Haplotype analysis showed that the c.628G>A splice mutation is associated with the same haplotype in our population.

Conclusions: Increased knowledge on phenotypical variability found in female aromatase-deficient patients is useful to improve the detection rate in this disorder. In our population, a genetic founder defect has probably contributed to an increase in the incidence of the c.628G>A splice mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2014-2967DOI Listing
February 2015

Fertility issues in the management of patients with disorders of sex development.

Endocr Dev 2014 9;27:87-98. Epub 2014 Sep 9.

Servicio de Endocrinología, Hospital de Pediatría 'Prof. Dr. Juan P. Garrahan', División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.

Fertility potential is one of the issues that should be considered by the multidisciplinary team when addressing gender assignment, surgical management, the process of disclosure to patients and their families, and prospective long-term outcomes of individuals with disorders of sex development (DSD). In this article, we review the current evidence of the fertility potential of patients with: (1) dysgenetic DSD, including pure and partial gonadal dysgenesis, asymmetric gonadal differentiation, ovotesticular DSD and 46,XX testicular DSD; (2) 46,XY DSD due to abnormal testicular hormone production or action, including testosterone production deficiencies, dihydrotestosterone deficiency, androgen insensitivity and defects in anti-Müllerian hormone or its receptor, and (3) 46,XX DSD due to excessive androgen exposure in individuals with no testicular tissue, i.e. congenital adrenal hyperplasia and aromatase deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000363633DOI Listing
June 2015

Three novel IGF1R mutations in microcephalic patients with prenatal and postnatal growth impairment.

Clin Endocrinol (Oxf) 2015 May 7;82(5):704-11. Epub 2014 Aug 7.

Endocrinology Service, Hospital de Pediatría Garrahan, Buenos Aires, Argentina.

Background: IGF1R gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation, and microcephaly.

Objective: To identify and characterize IGF1R gene variations in a cohort of 28 Argentinean children suspected of having IGF-1 insensitivity, who were selected on the basis of the association of pre/postnatal growth failure and microcephaly.

Methods: The coding sequence and flanking intronic regions of IGF1R gene were amplified and directly sequenced. Functional characterization was performed by two in vitro assays: 1) [Methyl-(3) H] thymidine incorporation into DNA in fibroblast cell primary cultures from patients and controls treated with IGF-1 for 16-24 h. 2) PI3K/Akt pathway was evaluated with phospho-Akt (Ser473) STAR ELISA Kit (Millipore) in fibroblast cultures from patients and controls stimulated with IGF-1 for 10 min. Prepubertal clinical and GH-IGF-1 axis evaluation was followed up.

Results: We identified three novel heterozygous missense mutations in three unrelated patients, de novo p.Arg1256Ser, de novo p.Asn359Tyr and p.Tyr865Cys. In control cells, proliferation assay showed that IGF-1 significantly induced DNA synthesis at 20 h and Akt phosphorylation assay that it significantly stimulated phosphorylation after 10 min (P < 0·05 by anova and Bonferroni Tests). However, no significant increase was observed in any of the three patient fibroblasts in both functional studies. GH therapy growth response in two patients was inconsistent.

Conclusion: These variations led to failure of the IGF1R function causing pre- and postnatal growth retardation and microcephaly. Microcephaly should be considered in the evaluation of SGA patients, because it seems to favour the frequency of detection of IGF1R mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cen.12555DOI Listing
May 2015

[Novel heterozygous mutation in the steroidogenic acute regulatory protein gene in a 46,XY patient with congenital lipoid adrenal hyperplasia].

Medicina (B Aires) 2013 ;73(4):297-302

Servicio de Endocrinología, Hospital Nacional de Pediatría Juan P. Garrahan, Buenos Aires, Argentina.

StAR facilitates cholesterol entry into the mitochondria as part of the transduceosome complex. Recessive mutations in the gen STAR cause classic and nonclassic congenital lipoid adrenal hyperplasia. The aim of the study was to analyze the molecular consequences of a novel heterozygous STAR mutation in a 46,XY patient with ambiguous genitalia and adrenal insufficiency. We found a de novo heterozygous IVS-2A>G STAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1 and TSPO genes. RT-PCR and sequencing from patient's testicular RNA showed a -exon2 transcript and the wild-type (WT) transcript. Both 37 kDa precursor and 30 kDa mature protein were detected in COS-7 cell transfected with mutant and WT plasmids. Immunofluorescence showed almost no co-localization of mitochondria and mutant protein (delta22-59StAR). Delta22-59StAR activity was 65±13% of WT. Cotransfection with WT and delta22-59StAR plasmids reduced WT activity by 62.0% ± 13.9. Novel splice-junction heterozygous STAR mutation (IVS-2A>G) resulted in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. A misfolded p.G22_L59delStAR might interfere with WT StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2014

Unique dominant negative mutation in the N-terminal mitochondrial targeting sequence of StAR, causing a variant form of congenital lipoid adrenal hyperplasia.

J Clin Endocrinol Metab 2013 Jan 21;98(1):E153-61. Epub 2012 Nov 21.

Endocrine Service, Hospital de Pediatria Garrahan, Buenos Aires C1245AAM, Argentina.

Context: Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part of the transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutations cause classic and nonclassic congenital lipoid adrenal hyperplasia.

Objective: The aim of this study was to report the clinical, hormonal, genetic, and functional data of a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguous genitalia and neonatal severe steroidogenic deficiency.

Patient: Undetectable serum steroids with high ACTH and plasma renin activity but normal acute GnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosterone were undetectable, whereas FSH was normal but increased slowly afterward. Estrogen replacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after 1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisone withdrawal because of hypertension, plasma renin activity and aldosterone remained normal, suggesting mineralocorticoid recovery by a StAR-independent mechanism.

Results: We found a de novo heterozygous IVS-2A>G StAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. The mutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StAR activity in a dominant-negative manner and almost no mitochondria localization.

Conclusions: A misfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. We speculated that estrogen might have modulated mineralocorticoid function and pubertal maturation in a human natural model lacking endogenous steroid production.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2012-2865DOI Listing
January 2013

Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred.

Horm Res Paediatr 2012 14;78(2):119-26. Epub 2012 Aug 14.

Endocrinology Service, Hospital de Pediatría Garrahan, Buenos Aires, Argentina.

In humans, steroidogenic factor 1 (NR5A1/SF-1) mutations have been reported to cause gonadal dysgenesis, with or without adrenal failure, in both 46,XY and 46,XX individuals. We have previously reported extreme within-family variability in affected 46,XY patients. Even though low ovarian reserve with preserved fertility has been reported in females harboring NR5A1 gene mutations, fertility has only been observed in one reported case in affected 46,XY individuals. A kindred with multiple affected members presenting gonadal dysgenesis was studied. Four 46,XY individuals presented severe hypospadias at birth, one of them associated with micropenis and cryptorchidism. The other 3 developed spontaneous male puberty, and 1 has fathered 5 children. Four 46,XX patients presented premature ovarian failure (one of them was not available for the study) or high follicle-stimulating hormone levels. Mutational analysis of the NR5A1 gene revealed a novel heterozygous mutation, c.938G→A, predicted to cause a p.Arg313Hys amino acid change. A highly conserved amino acid of the ligand-binding domain of the mature protein is affected, predicting abnormal protein function. We confirm that preserved fertility can be observed in patients with a 46,XY disorder of sex development due to heterozygous mutations in the NR5A1 gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000338346DOI Listing
February 2013

Effectiveness of rhGH treatment on final height of renal-transplant recipients in childhood.

Pediatr Nephrol 2012 Jun 26;27(6):1005-9. Epub 2012 Jan 26.

Department of Endocrinology, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.

Background: Growth retardation is a considerable clinical problem in children with chronic kidney disease (CKD). Optimization of metabolic and nutritional parameters does not always lead to improved growth. Recombinant human growth hormone (rhGH) treatment has been used to improve height. Several studies in the literature have shown increased growth velocity, although data on the final height (FH) reached are scarce.

Aims: We assessed the effect of rhGH on FH standard deviation score (SDS) in children with CKD following renal transplantation (RTx), comparing it with patients who did not receive rhGH (control group) but were treated with the same protocol and followed up in a single Center.

Methods: Thirty-three patients received rhGH treatment until FH. Fourteen who refused rhGH therapy were included in the controls. Prognostic factors for FH and changes in glomerular filtration rate (GFR) during follow-up were also analyzed

Results: FH SDS in rhGH-treated patients was significantly higher than in controls (-1.88 ± 1.14 vs -3.48 ± 1.19 SDS, respectively, p <0.05). In both groups, a similar reduction in GFR was observed. Height (SDS) at onset of rhGH treatment was the only statistically significant variable useful to predict response to treatment (p = 0.001).

Conclusion: Our findings confirm that rhGH is effective to improve FH in CKD RTx patients, without affecting kidney function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-011-2090-8DOI Listing
June 2012

Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia.

Clin Endocrinol (Oxf) 2011 Oct;75(4):427-35

Endocrinology Service, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.

Objective: To report genotype-phenotype correlation in a large cohort of patients.

Context: Study of the CYP21A2 gene in 866 unrelated chromosomes of 21-hydroxylase deficiency in Argentinean patients with classic and nonclassic (NC) forms of congenital adrenal hyperplasia (CAH).

Methods: Eleven most common mutations were analysed by allele-specific polymerase chain reaction, restriction fragment length polymorphism (RFLP) or southern blot analysis. Gene sequencing was performed when no mutation was detected in one allele or the genotype-phenotype correlation was lacking.

Results: The 11-most-common-mutation screening allowed for the detection of 88·1% of affected alleles (80·3% in the NC and 95·2% in the classic forms). p.V281L, IVS2-13A/C>G (In2) and gene deletions and large gene conversions were the most prevalent mutations. In2 (35·2%) in salt wasting (SW), p.I172N (37·3%) in simple virilizing and p.V281L (54·1%) in NC CAH were the most prevalent mutations within the clinical forms. In 7/15 p.P30L mutation alleles, a chimeric CYP21A1P/CYP21A2 gene [PromCYP21A1P; p.P30L] was detected, while 6/15 represented a single-nucleotide substitution, and in 2/15 linkage with mutations, p.[P30L; V281L] and [p.P30L; IVS2-13A/C > G; p.Q318X] was found. In two SW patients, a novel nonsense mutation, p.Q41X, was observed. In three p.V281L mutation patients, the phenotype was more severe than predicted by genotype. Sequence analysis revealed an intronic alteration in the allele carrying the p.V281L mutation [IVS2 + 5G > A; p.V281L]. An aberrant splicing in this p.V281L mutated allele explains the clinical phenotype.

Conclusions: A high percentage of CYP21A2 affected alleles is detected by the 11-mutation screening study. Genotype-phenotype correlation was high, but when the phenotype is more severe than predicted by genotype, presence of two alterations in one allele should be ruled out.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2265.2011.04123.xDOI Listing
October 2011

Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects.

Horm Res Paediatr 2011 22;75(1):70-7. Epub 2010 Sep 22.

Endocrinology Service, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.

Background: Three novel heterozygous SF-1 gene mutations affecting multiple members of two unrelated families with a history of 46,XY disorders of sex development (DSD) and 46,XX ovarian insufficiency are described.

Methods: clinical and mutational analysis of the SF-1 gene in 9 subjects of two families.

Results: family 1 had 2 affected 46,XY DSD subjects. One, born with severe perineal hypospadias, was raised as a male, and presented normal adolescence. The other, born with ambiguous genitalia, uterus, and mild testicular dysgenesis, was raised as a female. A W279X heterozygous mutation and an intronic deletion (g3314-3317delTCTC (IVS 4 + 8) was found in the SF-1 gene. In family 2, 4/6 affected siblings had 46,XY DSD or hypospadias. An affected 46,XX sister had normal sexual development but increased FSH levels. The 37-year-old affected mother had entered menopause. An Y183X heterozygous mutation was detected.

Conclusion: an extreme within-family phenotypic variability, ranging from severe prenatal undervirilization to normal pubertal development, was observed in 46,XY-affected siblings, indicating that other unknown factors might be involved in the phenotype. Low ovarian reserve and preserved fertility in 46,XX subjects can be observed in heterozygous SF-1 gene mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000320029DOI Listing
May 2011

Metformin, estrogen replacement therapy and gonadotropin inhibition fail to improve insulin sensitivity in a girl with aromatase deficiency.

Horm Res 2009 21;72(6):370-6. Epub 2009 Oct 21.

Endocrine Service, Hospital de Pediatría Garrahan, Buenos Aires, Argentina.

Background: Insulin resistance (IR), abnormal lipid profile, and other features of the metabolic syndrome have been described in CYP19 gene knockout mice and in aromatase-deficient adult men but not in prepubertal affected girls.

Aims: To study insulin sensitivity, as well as the effects of estrogen, metformin and GnRHa treatment on glucose homeostasis, in an aromatase-deficient girl.

Methods: Clinical, metabolic and hormonal follow-up data, from 8 to 12 years of age, is presented.

Results: At 9 years of age, IR (HOMA 5.6) and glucose intolerance was detected, along with high serum testosterone (2.28 nmol/l), androstenedione (4.92 nmol/l) and FSH (13.4 mIU/ml) levels. Estrogen replacement was ineffective to suppress gonadotropin and androgen levels, as well as IR. Under metformin therapy, she developed type 2 diabetes and acanthosis nigricans. GnRHa administration for 1 year resulted in marked decreases in gonadotropin and serum androgens, but severe IR persisted.

Conclusion: Postnatal estrogen replacement and a marked decrease of endogenous androgens failed to improve IR and glucose tolerance. We propose that, in females, the increment of androgens and/or lack of estrogens during fetal life might alter the mechanism of fetal programming of insulin sensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000249165DOI Listing
February 2010

Hydrocortisone treatment in girls with congenital adrenal hyperplasia inhibits serum dehydroepiandrosterone sulfate and affects the GH-IGF-I system.

J Pediatr Endocrinol Metab 2009 Mar;22(3):255-61

Hospital de Pediatría Garrahan, Endocrinology Service, Buenos Aires, Argentina.

Sex hormones are modulators of the GH/ IGF-I system. We have hypothesized that the inhibition of DHEAS in treated girls with congenital adrenal hyperplasia (CAH) might affect this modulation. We analyzed serum IGF-I, IGFBP-3 and DHEAS in 17 prepubertal (Pp) and 32 pubertal (Pu) girls with CAH, under hydrocortisone replacement therapy, in the presence of normal (Gr1) or high (Gr2) serum testosterone (T) and androstenedione (A) levels. All groups had appropriate normal controls. Serum DHEAS in patients with CAH was significantly lower than in the respective controls (p < 0.04), except for Pp CAH Gr2. Serum IGF-I, but not serum IGFBP-3, in CAH subgroups was significantly higher than in the respective controls (p < 0.05), except for Pp CAH Gr2. It is concluded that glucocorticoid treatment of girls with CAH results in hypofunction of the adrenal zona reticularis. Low levels of serum DHEAS could be involved in the regulation of IGF-I biological response in target tissues. Additional studies are necessary to confirm these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem.2009.22.3.255DOI Listing
March 2009

Adrenarche: postnatal adrenal zonation and hormonal and metabolic regulation.

Horm Res 2008 30;70(5):257-67. Epub 2008 Sep 30.

Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina.

Adrenarche is the direct consequence of the organogenesis of the zona reticularis (ZR). Proliferation of cortical cells could take place in the outermost layers of the adrenal cortex. Cells could then migrate to differentiate the zona glomerulosa (ZG) and zona fasciculata (ZF) during fetal life, and the ZR during postnatal life. After adrenarche, there are detectable increases in circulating DHEA and DHEA-S. Adrenarche could result from an increase in 17,20-lyase activity of P450c17 secondary to high levels of cytochrome b(5) expression, and from a decrease in 3betaHSD2 expression along with an increase in the expression of SULT2A1 in the ZR. The GH-IGF system and insulin, among other factors, might also modulate adrenal androgen production. Furthermore, high concentrations of estradiol enhance basal and ACTH-stimulated DHEA-S production, while aromatase expression was observed in the human adrenal medulla but not in the ZR, suggesting that estrogens produced in the adrenal medulla might be involved in the regulation of androgen production in the ZR. Premature adrenarche might be associated with ovarian hyperandrogenism and polycystic ovarian syndrome in females, as well as with insulin resistance in both sexes. However, many questions remain, transforming adrenal androgens into markers of diseases important for human health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000157871DOI Listing
January 2009

Expression of the IGF and the aromatase/estrogen receptor systems in human adrenal tissues from early infancy to late puberty: implications for the development of adrenarche.

Rev Endocr Metab Disord 2009 Mar;10(1):51-61

Endocrinology Department, Garrahan Pediatric Hospital, Buenos Aires, Argentina.

Adrenarche is a process of postnatal sexual maturation occurring in higher primates, in which there is an increase in the secretion of adrenal androgens. It is the consequence of a process of postnatal organogenesis characterized by the development of a new zone in the adrenal cortex, the zona reticularis (ZR). The mechanism of this phenomenon remains poorly understood, suggesting that it might be a multifactorial event. A relationship between circulating IGF-I, insulin sensitivity, and adrenal androgens has been postulated. Boys and girls have different patterns of changes in insulin sensitivity at puberty, perhaps secondary to differences in the estrogen milieu. Estrogen effects may also play a role in premature adrenarche. Peripheral or local IGF-1 actions could regulate adrenal progenitor cell proliferation and migration. Since adrenal progenitor cells as well as IGF-I and the IGF-R1 are located in the outer zone of the adrenal cortex during childhood and adolescence, this peripheral cell layer, below the capsule, may contain undifferentiated progenitor cells. Therefore, the IGF-R1 signaling pathway might positively modulate the proliferation and migration of adrenal progenitor cell to stimulate the development of adrenal zones, including ZR. However, no evidence of a direct action of IGF-I on ZR was found. In addition, a role for estrogens in the ontogenesis of ZR is suggested by the presence of aromatase (CYP19) in the subcapsular zona glomerulosa and in the adrenal medulla. Estrogens produced locally could act on ZR by interacting with estrogen receptor beta (ERbeta), but not alpha, and membrane estrogen receptor GPR-30. An estradiol-induced increase in DHEA/cortisol ratio was indeed seen in cultures of adrenocortical cells from post-adrenarche adrenals. In summary, several lines of evidence point to the action of multiple factors, such as local adrenal maturational changes and peripheral metabolic signals, on postnatal human adrenal gland ZR formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11154-008-9105-1DOI Listing
March 2009

[Exon 5 alternative splicing of the cytochrome P450 aromatase could be a regulatory mechanism for estrogen production in humans].

Medicina (B Aires) 2007 ;67(4):369-73

Laboratorio de Investigación, Hospital Garrahan, Buenos Aires, Argentina.

P450 aromatase (P450Aro), involved in androgen to estrogen conversion, is encoded by the CYP19 gene. P450Aro c655G>A mutation described in heterozygous form in a girl and in homozygous form in an adult male with P450Aro deficiency results in an aberrant splicing due to disruption of a donor splice site. A truncated inactive protein would be expected if intron5 is retained. Surprisingly, the girl described with this mutation showed spontaneous breast development and pubertal estradiol (E2) levels suggesting residual P450Aro activity (AA). Formerly, we postulate the in frame E5 skipping as a consequence of this mutation generating a protein with some degree of activity. When P450Aro mRNA expression was analysed from patient's lymphocytes, an aberrant spliced mRNA lacking E5 (-E5mRNA) was detected, suggesting an association between E5 skipping and the presence of the mutation. Splicing assays in Y1 cells confirmed this association. -Ex5 cDNA expression in Y1 cells resulted in an inactive protein that could not explain patient's phenotype. Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to splicing mutations and physiological alternative splicing (AS) events. Therefore, -Ex5mRNA was assessed as a natural occurring alternative transcript in normal human steroidogenic tissues. As P450Aro -E5mRNA expression was detected in human term placenta, prepubertal testis and prepubertal adrenal, we might speculate that AS of P450Aro coding region would occur in humans and would be involved in the complex AA regulation. Furthermore, tissue specific regulation of AS might suggest low expression of +E5mRNA from the c655G>A allele explaining residual AA evidenced in the affected girl.
View Article and Find Full Text PDF

Download full-text PDF

Source
September 2008

The cytochrome P450 aromatase lacking exon 5 is associated with a phenotype of nonclassic aromatase deficiency and is also present in normal human steroidogenic tissues.

Clin Endocrinol (Oxf) 2007 Nov 2;67(5):698-705. Epub 2007 Jul 2.

Molecular Biology Laboratory, Endocrinology Department, J. P. Garrahan Paediatric Hospital, Buenos Aires, Argentina.

Objective: The previously described c655G>A mutation of the human cytochrome P450 aromatase gene (P450aro, CYP19) results in aberrant splicing due to disruption of a donor splice site. To explain the phenotype of partial aromatase deficiency observed in a female patient described with this mutation, molecular consequences of the c655G>A mutation were investigated.

Design: To investigate whether the c655G>A mutation causes an aberrant spliced mRNA lacking exon 5 (-Ex5), P450aro RNA was analysed from the patient's lymphocytes by reverse transcription polymerase chain reaction (RT-PCR) and by splicing assays performed in Y1 cells transfected with a P450aro -Ex5 expression vector. Aromatase activity of the c655G>A mutant was predicted by three dimensional (3D) protein modelling studies and analysed in transiently transfected Y1 cells. Exon 5 might be predicted as a poorly defined exon suggesting a susceptibility to both splicing mutations and physiological alternative splicing events. Therefore, expression of the -Ex5 mRNA was also assessed as a possibly naturally occurring alternative splicing transcript in normal human steroidogenic tissues.

Patients: An aromatase deficient girl was born with ambiguous genitalia. Elevated serum LH, FSH and androgens, as well as cystic ovaries, were found during prepuberty. At the age of 8.4 years, spontaneous breast development and a 194.6 pmol/l serum oestradiol level was observed.

Results: The -Ex5 mRNA was found in lymphocytes of the P450aro deficient girl and her father, who was a carrier of the mutation. Mutant minigene expression resulted in complete exon 5 skipping. As expected from 3D protein modelling, -Ex5 cDNA expression in Y1 cells resulted in loss of P450aro activity. In addition, the -Ex5 mRNA was present in placenta, prepubertal testis and adrenal tissues.

Conclusions: Alternative splicing of exon 5 of the CYP19 gene occurs in the wild type (WT) as well as in the c655G>A mutant. We speculate that for the WT it might function as a regulatory mechanism for aromatization, whereas for the mutant a relative prevalence of the shorter over the full-length protein might explain the phenotype of partial aromatase deficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-2265.2007.02948.xDOI Listing
November 2007

Hypothalamic-pituitary-ovarian axis during infancy, early and late prepuberty in an aromatase-deficient girl who is a compound heterocygote for two new point mutations of the CYP19 gene.

J Clin Endocrinol Metab 2003 Nov;88(11):5127-31

Laboratorio de Investigación, Hospital de Pediatría Garrahan, Buenos Aires, Argentina 1245.

A loss of function mutation of the CYP19 aromatase gene leads to excess circulating androgens in the fetus and in the mother, resulting in ambiguous genitalia in the female fetus. Later on, lack of aromatase is responsible for sexual infantilism, primary amenorrhea, tall stature, and multicystic ovaries, even in preadolescent girls. Up to now, 11 CYP19 aromatase point mutations and 10 well-documented cases have been reported. In the present case, we are reporting the clinical and hormonal follow-up, from birth to 7 yr of age, of an affected girl with ambiguous genitalia. Gene analysis showed that she was a compound heterozygote for two new CYP19 aromatase point mutations. In the father's allele, there was a consensus 5' splice donor sequence mutation, GAA-AAA at cDNA position bp 655 in exon 5, which probably results in a cryptic donor site. In the mother's allele, there was a base A deletion in exon 9 (Delta A GLU 412X), causing a frame shift mutation, and a stop codon after 98 bp (33 codons) downstream, altering the critical heme-binding region. Basal serum LH and FSH levels were high at 8 d of age (42.9 and 51.3 U/liter), 26 d of age (76.2 and 119 U/liter), and 60 d of age (58.7 and 150 U/liter, respectively). Both gonadotropins dropped dramatically between the second and fifth months of age (to 1.79 and 14.9 U/liter) but remained higher than in normal control girls (0.64 and 8.5 U/liter, respectively). Serum testosterone (T) and androstenedione (Delta(4)A) levels were high during the first month, but Delta(4)A was normal at 2 months of age. However, at 5 months of age, along with significant decrements of serum LH and FSH levels and increments in serum Delta(4)A and T levels, a large ovarian cyst was removed from each gonad. Relatively high levels of T [27.3 ng/ml (94.6 nmol/liter); control, 34.9 ng/ml (121 nmol/liter)], but not of estradiol [1.8 ng/ml (6.6 nmol/liter); control 62.9 ng/ml (231 nmol/liter)], and a high T/estradiol ratio [15.2; control < 1] were found in the follicular fluid. Serum Delta(4)A and T levels remained normal from 1-5 yr of age, but they were high at the last visit (late prepuberty). A GnRH test was performed at 3.9, 6, and 7.1 yr of age. At 3.9 yr, a low prepubertal serum LH peak (2.12 U/liter) was found, but at the older ages, higher serum LH peaks (8.25 and 22.5 U/liter, respectively) were observed. Growth pattern and body mass index were normal, but after the age of 5.2 yr, delays in bone age greater than 2 yr were observed. We concluded that: 1) these two new CYP19 aromatase gene mutations are responsible for the phenotype of aromatase deficiency; 2) in girls, aromatase deficiency results in a decrease of the negative feedback of both serum LH and FSH, which can be detected as early as the second week after birth and persists up to the sixth month of life, and of FSH during the rest of prepuberty; and 3) because large ovarian cysts developed when serum LH and FSH dropped, aromatization of androgens might be required to prevent formation of cystic ovaries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2003-030433DOI Listing
November 2003

Relationship between the growth hormone/insulin-like growth factor-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal girls.

J Clin Endocrinol Metab 2003 Mar;88(3):1389-93

Endocrinology Service, Garrahan Pediatric Hospital, Buenos Aires, C1245AAM, Argentina.

The aim of this study was to analyze the possible implication of changes in the GH/IGF-I axis and in insulin sensitivity for the regulation of adrenal androgen secretion of normal prepubertal and adolescent girls. A total of 61 normal girls were evaluated in prepuberty [Group (Gr)1, n = 33; early (Gr1A, n = 16) and late (Gr1B, n = 17)]; puberty (Gr3, n = 28), early (Gr3A, n = 9) and late (Gr3B, n = 19); and during the transition between prepuberty and puberty (Gr2, n = 26). Insulin sensitivity was estimated by the fasting glucose/insulin ratio (G/I). In Gr1, G/I was significantly higher, and the mean serum IGF-I and serum dehydroepiandrosterone sulfate (DHEAS) were significantly lower than in Gr3 (P < 0.0001). Mean G/I in Gr1A and Gr3A was significantly higher than in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively, and ratios in Gr1B were also significantly higher than in Gr3A (P < 0.02). However, body mass index (BMI) in Gr1A, Gr1B, and Gr3A was not significantly different, although a significant increment was observed between late prepuberty (Gr1B) and late puberty (Gr3B; P < 0.0001). On the other hand, serum IGF-I levels in Gr1A and Gr3A were significantly lower than those in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively. The mean serum DHEAS level in Gr1A and Gr3A was significantly lower than in Gr1B (P < 0.01) and Gr3B (P < 0.02), respectively, and the level in Gr1B was also significantly lower than in Gr3A (P < 0.02). Correlation studies within Gr1, Gr2, and Gr3 were also performed. There was a significant positive correlation between serum DHEAS and age and a significant negative correlation between serum DHEAS and G/I in the three groups. However, a significant positive correlation between serum DHEAS and serum IGF-I was only found in Gr1. Furthermore, a significant negative correlation between BMI and the G/I was found in Gr2 and Gr3. Therefore, changes in insulin sensitivity might be involved in adrenal androgen synthesis both in prepuberty and in puberty, as well as during the transition from prepuberty to puberty. Changes in BMI suggest that adiposity might be a mediator of this effect, particularly during late puberty. On the other hand, the GH/IGF axis might be an important metabolic signal involved in the maturational changes of human adrenal androgens during prepuberty, at the time of adrenarche. Indeed, a significant negative correlation between G/I and serum IGF-I was found in Gr1, as well as in Gr2. In conclusion, the findings of this study indicate that the GH/IGF-I axis and insulin resistance might be involved in the mechanism of adrenarche during prepuberty in normal girls. Because these relationships had not been seen in boys, we proposed that prepubertal ovarian estrogens might be responsible for the sex difference. The relationship between insulin resistance and adrenal androgens persists during the transition from prepuberty to puberty, as well as during puberty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2002-020979DOI Listing
March 2003

Relationship between the GH/IGF-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal boys.

J Clin Endocrinol Metab 2002 Mar;87(3):1162-9

Endocrinology Service, Garrahan Pediatric Hospital, Buenos Aires C1245AAM, Argentina.

In girls, but not in boys, pronounced adrenarche and precocious pubarche along with ovarian hyperandrogenism have been related to insulin resistance and reduced fetal growth. However, insulin secretion is increased during puberty in normal boys. The aim of this study was to analyze the possible implication of changes in the GH/IGF-I axis and in insulin sensitivity for the regulation of adrenal androgen secretion of normal prepubertal and adolescent boys. Fifty-six normal boys were divided into the following groups (Gr): Gr1, prepuberty (testicular volume, <4 cc; n = 33); and Gr3, puberty (testicular volume, 4-25 cc; n = 23). Gr1 was subdivided according to age into: Gr1A, early prepuberty (boys younger than 5.9 yr old; n = 16); and Gr1B, late prepuberty (prepubertal boys, 5.9 yr old or older; n = 17). Gr3 was subdivided according to testicular volume into: Gr3A, early puberty (testicular volume, 4-8 cc; n = 13); and Gr3B, late puberty (testicular volume, 10--25 cc; n = 10). To study hormonal changes during the transition between prepuberty and puberty, an additional group, Gr2 (n = 30), was defined by mixing Gr1B and Gr3A. Serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (Delta(4)A), insulin, IGF-I, and glucose were determined after overnight fasting. Insulin sensitivity was estimated by the fasting glucose/insulin (G/I) ratio. There was a close correlation between fasting G/I ratio and QUICKI, a quantitative insulin sensitivity check index. Mean values for Gr1 and Gr3 as well as their subgroups were compared using t test. In Gr1, the mean fasting G/I ratio was significantly higher, and the mean serum IGF-I, serum DHEAS, and serum Delta(4)A levels were significantly lower than in Gr3 (P < 0.001). Mean fasting G/I ratios in Gr1A and Gr3A were not significantly different from those in Gr1B and Gr3B, respectively, but the fasting G/I ratio in Gr3A was significantly lower than that in Gr1B (P < 0006). Moreover, body mass index (BMI) in Gr3A was significantly higher than that in Gr1B (P < 0.01). On the other hand, mean serum IGF-I levels in Gr1A and Gr3A were significantly lower than those in Gr1B and Gr3B, respectively (P < 0.0001). The mean serum DHEAS level in Gr1A was significantly lower than that in Gr1B (P < 0.01), but no difference was found between Gr3A and Gr3B. The mean serum Delta(4)A in Gr1A was similar to that in Gr1B, but the mean serum Delta(4)A in Gr3A was significantly lower than that in Gr3B (P = 0.0001). Correlation studies within Gr1, Gr2, and Gr3 were also carried out. There was a significant positive correlation between serum DHEAS and age in Gr1 and Gr2, but not in Gr3. In Gr1, no significant correlation was found between serum DHEAS and fasting G/I ratio or between serum DHEAS and serum IGF-I, suggesting that adrenal steroidogenesis in male prepuberty is independent of insulin sensitivity or peripheral IGF-I. In Gr2, a significant negative correlation (P = 0.01) between serum DHEAS and the fasting G/I ratio was found, but not between serum DHEAS and serum IGF-I. Furthermore, a significant negative correlation between BMI and the fasting G/I ratio was also found. Therefore, changes in insulin sensitivity might be involved in adrenal androgen synthesis during the transition from prepuberty to puberty. Finally, in Gr3, DHEAS was not significantly correlated with the fasting G/I ratio or serum IGF-I. A significant negative correlation between serum Delta(4)A and the fasting G/I ratio was found in Gr2. In Gr2, but not in Gr3, there was a significant negative correlation between the fasting G/I ratio and age (P = 0.03) and between the fasting G/I ratio and serum IGF-I (P = 0.03). In conclusion, our data support the hypothesis that the GH/IGF-I axis and insulin sensitivity are not involved in the mechanism of adrenarche in boys. Insulin sensitivity and BMI, however, decrease at early puberty rather than at late puberty, and this change could be involved in modulating adrenal androgen steroidogenesis during the transition between late prepuberty and early puberty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jcem.87.3.8330DOI Listing
March 2002