Human prepubertal aromatase deficiency: physiological and pathophysiological lessons learned from this experiment of nature

En els humans, el cP450arom és el producte d'un gen únic (CYP19), localitzat en el cromosoma 15q21.1. A la placenta, l'aromatització activa dels andrògens protegeix el fetus femella i la mare de les accions virilitzants dels andrògens fetals. De fet, els nadons 46XX amb deficiència completa de l'aromatasa neixen amb una ambigüitat dels genitals externs. Els estudis en pacients afectats per la deficiència completa del cP450arom han contribuït considerablement a l'anàlisi de la importància de l'activitat de la cP450arom en la diferenciació sexual, en el patró de secreció de les gonadotrofines, en la capacitat reproductora, en el metabolisme lipídic i la sensibilitat a la insulina, i en el creixement i la maduració esquelètica, en ambdós sexes. La seqüència codificant de la proteïna està continguda en nou exons (exons 2-10), que s'estenen aproximadament al llarg de 35 kb de DNA. Els codons d'iniciació i terminació de la traducció són als exons 2 i 10, respectivament. Fins ara, s'han documentat onze casos de deficiència completa de l'aromatasa secundaris en mutacions del gen CYP19. El patró dels nivells sèrics hormonals indica una baixa concentració d'estrògens i alta d'andrògens, FSH, i, ocasionalment, també d'LH, sempre, però, depenent de l'edat i del sexe. Durant la infantesa, s'observa un dimorfisme sexual en el paper dels estrògens en la regulació de la secreció de les gonadotrofines. Aquests pacients presenten un risc elevat de desenvolupar quists d'ovari, fins i tot abans de la pubertat. Finalment, l'estudi d'aquests pacients també ha estat útil per ill. ustrar el paper dels estrògens en el desenvolupament esquelètic, en la maduració de les epífisis i en el brot de creixement puberal, en ambdós sexes.In humans, cP450arom appears to be the product of a single gene (CYP19), located on chromosome 15q21.1. In the placenta, the active aromatization of androgens protects the female fetus and the mother from the virilizing actions of fetal androgens. Indeed, 46, XX neonates with complete aromatase deficiency are born with ambiguous external genitalia. Studies carried out on patients with complete cP450arom deficiency have also contributed considerably to the analysis of the importance that cP450arom activity has on sexual differentiation, the pattern of gonadotropin secretion, reproductive capacity, lipid metabolism and insulin sensitivity, as well as growth and skeletal maturation in both sexes. The protein coding sequence is contained within nine exons (exons 2-10), which span approximately 35 kb of DNA. The translation, initiation and termination codons are present in exons 2 and 10, respectively. Eleven welldocumented cases of complete aromatase deficiency, secondary to mutations of the CYP19 gene, have been reported. Very low estrogens and high androgens, FSH, and sometimes LH, depending on age and sex, characterize the pattern of serum hormones. During infancy, a sexual dimorphism has been observed in the role that estrogens play in the regulation of gonadotropins. These patients are at risk of developing ovarian cysts, even before puberty. Finally, the study of these patients has also been useful to illustrate the essential role of estrogens in skeletal development, epiphysial maturation, and in the pubertal growth spurt in both sexes

Conceptos y estrategias aplicadas a la pesquisa neonatal de endocrinopatías

Los programas de Pesquisa Neonatal son programas de salud pública destinados a la identificación de condiciones médicas que, de mediar una intervención oportuna y temprana, permitirían eliminar o reducir mortalidad, morbilidad o discapacidades. El Hipotiroidismo Congénito (HC) y la Hiperplasia Suprarrenal Congénita (HSC) se encuentran entre las patologías cuya detección tiene un alto impacto para la salud pública y una relación costo / beneficio altamente favorable. El HC es una enfermedad severa, de incidencia elevada, sin signos clínicos evidentes en el período neonatal y su detección y tratamiento temprano permite prevenir el retardo mental profundo. El diagnóstico precoz de las HSC permite prevenir la crisis adrenal por pérdida salina con riesgo de shock hipovolémico y muerte o por stress, que puede ocurrir en la forma perdedora de sal que no ha sido reconocida, evitar la asignación errónea del sexo masculino en niñas recién nacidas virilizadas y prevenir los daños físicos y emocionales causados por el exceso de andrógenos (pubertad precoz, baja talla adulta). La pesquisa masiva de estas enfermedades ha supuesto desafios para superar inconvenientes de sensibillidad y especificidad de las técnicas, y se han desarrollado diferentes estrategias que son tratadas en el presente artículo. Asimismo, es de destacar el carácter multidisciplinario de este campo, y el rol clave del médico pediatra, quien debe participar activamente en la vigilancia clínica de estas enfermedades, atento a ciertas limitaciones y casos especiales dentro de la pesquisa neonatal.Fil: Dratler, Dres G.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Herzovich, V.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Vaiani, E.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Tilitzky, S.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ribas, A.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Chaler, E.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Lazzati, J.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Belgorosky, Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

Human Breast Milk Contamination with Phthalates and Alterations of Endogenous Reproductive Hormones in Infants Three Months of Age

Phthalates adversely affect the male reproductive system in animals. We investigated whether phthalate monoester contamination of human breast milk had any influence on the postnatal surge of reproductive hormones in newborn boys as a sign of testicular dysgenesis. DESIGN: We obtained biologic samples from a prospective Danish–Finnish cohort study on cryptorchidism from 1997 to 2001. We analyzed individual breast milk samples collected as additive aliquots 1–3 months postnatally (n = 130; 62 cryptorchid/68 healthy boys) for phthalate monoesters [mono-methyl phthalate (mMP), mono-ethyl phthalate (mEP), mono-n-butyl phthalate (mBP), mono-benzyl phthalate (mBzP), mono-2-ethylhexyl phthalate (mEHP), mono-isononyl phthalate (miNP)]. We analyzed serum samples (obtained in 74% of all boys) for gonadotropins, sex-hormone binding globulin (SHBG), testosterone, and inhibin B. RESULTS: All phthalate monoesters were found in breast milk with large variations [medians (minimum–maximum)]: mMP 0.10 (< 0.01–5.53 μg/L), mEP 0.95 (0.07–41.4 μg/L), mBP 9.6 (0.6–10,900 μg/L), mBzP 1.2 (0.2–26 μg/L), mEHP 11 (1.5–1,410 μg/L), miNP 95 (27–469 μg/L). Finnish breast milk had higher concentrations of mBP, mBzP, mEHP, and Danish breast milk had higher values for miNP (p = 0.0001–0.056). No association was found between phthalate monoester levels and cryptorchidism. However, mEP and mBP showed positive correlations with SHBG (r = 0.323, p = 0.002 and r = 0.272, p = 0.01, respectively); mMP, mEP, and mBP with LH:free testosterone ratio (r = 0.21–0.323, p = 0.002–0.044) and miNP with luteinizing hormone (r = 0.243, p = 0.019). mBP was negatively correlated with free testosterone (r = −0.22, p = 0.033). Other phthalate monoesters showed similar but nonsignificant tendencies. CONCLUSIONS: Our data on reproductive hormone profiles and phthalate exposures in newborn boys are in accordance with rodent data and suggest that human Leydig cell development and function may also be vulnerable to perinatal exposure to some phthalates. Our findings are also in line with other recent human data showing incomplete virilization in infant boys exposed to phthalates prenatally

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

Objective:The aim of this study was the molecular characterization of the AR 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 AR 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 AR was detected in only 13 (43.3%). Molecular studies revealed other affected or carrier relatives in 87% of the index cases. The AR mutations were found spread along the whole coding sequence, with a higher prevalence in the ligand binding domain. Nine out of 23 (39%) AR mutations were novel. In 17% of patients with detected AR 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 AR mutation occurred significantly less than in CAIS patients.Conclusion:Improved knowledge of the components of the AR complex and signaling network might contribute to long term outcome and genetic counseling in AIS patients

Association between CYP19 gene SNP rs2414096 Polymorphism and polycystic ovary syndrome in Chinese women

<p>Abstract</p> <p>Background</p> <p>Several studies have reported the association of the SNP rs2414096 in the CYP19 gene with hyperandrogenism, which is one of the clinical manifestations of polycystic ovary syndrome (PCOS). These studies suggest that SNP rs2414096 may be involved in the etiopathogenisis of PCOS. To investigate whetherthe CYP19 gene SNP rs2414096 polymorphism is associated with the susceptibility to PCOS, we designed a case-controlled association study including 684 individuals.</p> <p>Methods</p> <p>A case-controlled association study including 684 individuals (386 PCOS patients and 298 controls) was performed to assess the association of SNP rs2414096 with PCOS. Genotyping of SNP rs2414096 was conducted by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method that was performed on genomic DNA isolated from blood leucocytes. Results were analyzed in respect to clinical test results.</p> <p>Results</p> <p>The genotypic distributions of rs2414096 (GG, AG, AA) in the CYP19 gene (GG, AG, AA) in women with PCOS (0.363, 0.474, 0.163, respectively) were significantly different from that in controls (0.242, 0.500, 0.258, respectively) (<it>P </it>= 0.001). E2/T was different between the AA and GG genotypes. Age at menarche (AAM) and FSH were also significantly different among the GG, AG, and AA genotypes in women with PCOS (P = 0.0391 and 0.0118, respectively). No differences were observed in body mass index (BMI) and other serum hormone concentrations among the three genotypes, either in the PCOS patients or controls.</p> <p>Conclusions</p> <p>Our data suggest that SNP rs2414096 in the CYP19 gene is associated with susceptibility to PCOS.</p

Insulinotropic Effect of the Non-Steroidal Compound STX in Pancreatic β-Cells

The non-steroidal compound STX modulates the hypothalamic control of core body temperature and energy homeostasis. The aim of this work was to study the potential effects of STX on pancreatic β-cell function. 1–10 nM STX produced an increase in glucose-induced insulin secretion in isolated islets from male mice, whereas it had no effect in islets from female mice. This insulinotropic effect of STX was abolished by the anti-estrogen ICI 182,780. STX increased intracellular calcium entry in both whole islets and isolated β-cells, and closed the KATP channel, suggesting a direct effect on β-cells. When intraperitoneal glucose tolerance test was performed, a single dose of 100 µg/kg body weight STX improved glucose sensitivity in males, yet it had a slight effect on females. In agreement with the effect on isolated islets, 100 µg/kg dose of STX enhanced the plasma insulin increase in response to a glucose load, while it did not in females. Long-term treatment (100 µg/kg, 6 days) of male mice with STX did not alter body weight, fasting glucose, glucose sensitivity or islet insulin content. Ovariectomized females were insensitive to STX (100 µg/kg), after either an acute administration or a 6-day treatment. This long-term treatment was also ineffective in a mouse model of mild diabetes. Therefore, STX appears to have a gender-specific effect on blood glucose homeostasis, which is only manifested after an acute administration. The insulinotropic effect of STX in pancreatic β-cells is mediated by the closure of the KATP channel and the increase in intracellular calcium concentration. The in vivo improvement in glucose tolerance appears to be mostly due to the enhancement of insulin secretion from β-cells

Latin American Consensus: Children Born Small for Gestational Age

72-87Cuatrimestra

Human prepubertal aromatase deficiency: physiological and pathophysiological lessons learned from this experiment of nature

En els humans, el cP450arom és el producte d'un gen únic (CYP19), localitzat en el cromosoma 15q21.1. A la placenta, l'aromatització activa dels andrògens protegeix el fetus femella i la mare de les accions virilitzants dels andrògens fetals. De fet, els nadons 46XX amb deficiència completa de l'aromatasa neixen amb una ambigüitat dels genitals externs. Els estudis en pacients afectats per la deficiència completa del cP450arom han contribuït considerablement a l'anàlisi de la importància de l'activitat de la cP450arom en la diferenciació sexual, en el patró de secreció de les gonadotrofines, en la capacitat reproductora, en el metabolisme lipídic i la sensibilitat a la insulina, i en el creixement i la maduració esquelètica, en ambdós sexes. La seqüència codificant de la proteïna està continguda en nou exons (exons 2-10), que s'estenen aproximadament al llarg de 35 kb de DNA. Els codons d'iniciació i terminació de la traducció són als exons 2 i 10, respectivament. Fins ara, s'han documentat onze casos de deficiència completa de l'aromatasa secundaris en mutacions del gen CYP19. El patró dels nivells sèrics hormonals indica una baixa concentració d'estrògens i alta d'andrògens, FSH, i, ocasionalment, també d'LH, sempre, però, depenent de l'edat i del sexe. Durant la infantesa, s'observa un dimorfisme sexual en el paper dels estrògens en la regulació de la secreció de les gonadotrofines. Aquests pacients presenten un risc elevat de desenvolupar quists d'ovari, fins i tot abans de la pubertat. Finalment, l'estudi d'aquests pacients també ha estat útil per ill. ustrar el paper dels estrògens en el desenvolupament esquelètic, en la maduració de les epífisis i en el brot de creixement puberal, en ambdós sexes.In humans, cP450arom appears to be the product of a single gene (CYP19), located on chromosome 15q21.1. In the placenta, the active aromatization of androgens protects the female fetus and the mother from the virilizing actions of fetal androgens. Indeed, 46, XX neonates with complete aromatase deficiency are born with ambiguous external genitalia. Studies carried out on patients with complete cP450arom deficiency have also contributed considerably to the analysis of the importance that cP450arom activity has on sexual differentiation, the pattern of gonadotropin secretion, reproductive capacity, lipid metabolism and insulin sensitivity, as well as growth and skeletal maturation in both sexes. The protein coding sequence is contained within nine exons (exons 2-10), which span approximately 35 kb of DNA. The translation, initiation and termination codons are present in exons 2 and 10, respectively. Eleven welldocumented cases of complete aromatase deficiency, secondary to mutations of the CYP19 gene, have been reported. Very low estrogens and high androgens, FSH, and sometimes LH, depending on age and sex, characterize the pattern of serum hormones. During infancy, a sexual dimorphism has been observed in the role that estrogens play in the regulation of gonadotropins. These patients are at risk of developing ovarian cysts, even before puberty. Finally, the study of these patients has also been useful to illustrate the essential role of estrogens in skeletal development, epiphysial maturation, and in the pubertal growth spurt in both sexes