HUMAN PREPUBERTAL AROMATASE DEFICIENCY . PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL LESSONS LEARNED FROM THIS EXPERIMENT OF NATURE

En els humans, el cP450arom es el producte d'un gen unic (CYP19), localitzat en el cromosoma 15q21.1. A la placenta, l'aromatitzacio activa dels androgens protegeix el fetus femella i la mare de les accions virilitzants dels androgens fetals. De fet, els nadons 46XX amb deficiencia completa de l'aromatasa neixen amb una ambiguitat dels genitals externs. Els estudis en pacients afectats per la deficiencia completa del cP450arom han contribuit considerablement a l'analisi de la importancia de l'activitat de la cP450arom en la diferenciacio sexual, en el patro de secrecio de les gonadotrofines, en la capacitat reproductora, en el metabolisme lipidic i la sensibilitat a la insulina, i en el creixement i la maduracio esqueletica, en ambdos sexes. La sequencia codificant de la proteina esta continguda en nou exons (exons 2-10), que s'estenen aproximadament al llarg de 35 kb de DNA. Els codons d'iniciacio i terminacio de la traduccio son als exons 2 i 10, respectivament. Fins ara, s'han documentat onze casos de deficiencia completa de l'aromatasa secundaris en mutacions del gen CYP19. El patro dels nivells serics hormonals indica una baixa concentracio d'estrogens i alta d'androgens, FSH, i, ocasionalment, tambe d'LH, sempre, pero, depenent de l'edat i del sexe. Durant la infantesa, s'observa un dimorfisme sexual en el paper dels estrogens en la regulacio de la secrecio 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 tambe ha estat util per ill. ustrar el paper dels estrogens en el desenvolupament esqueletic, en la maduracio de les epifisis i en el brot de creixement puberal, en ambdos sexes.

[1]  A. Bockisch,et al.  Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene. , 2002, The Journal of clinical endocrinology and metabolism.

[2]  A. Belgorosky,et al.  Apoptosis and proliferation of human testicular somatic and germ cells during prepuberty: high rate of testicular growth in newborns mediated by decreased apoptosis. , 2002, The Journal of clinical endocrinology and metabolism.

[3]  E. Simpson,et al.  An age-related ovarian phenotype in mice with targeted disruption of the Cyp 19 (aromatase) gene. , 2000, Endocrinology.

[4]  N. Harada,et al.  Aromatase deficiency caused by a novel P450arom gene mutation: impact of absent estrogen production on serum gonadotropin concentration in a boy. , 1999, The Journal of clinical endocrinology and metabolism.

[5]  C. Bondy,et al.  Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. , 1999, The Journal of clinical endocrinology and metabolism.

[6]  W. Boon,et al.  Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[7]  L. Wickert,et al.  Female Pseudohermaphroditism Associated with a Novel Homozygous G-to-A (V370-to-M) Substitution in the P-450 Aromatase Gene , 1998, Journal of pediatric endocrinology & metabolism : JPEM.

[8]  A. Belgorosky,et al.  Irreversible Increase of Serum IGF-1 and IGFBP-3 Levels in GnRH-Dependent Precocious Puberty of Different Etiologies: Implications for the Onset of Puberty , 1998, Hormone Research in Paediatrics.

[9]  K. Korach,et al.  Effect of testosterone and estradiol in a man with aromatase deficiency. , 1997, The New England journal of medicine.

[10]  P. Jaeger,et al.  Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood. , 1997, The Journal of clinical endocrinology and metabolism.

[11]  B C Gladen,et al.  Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility. , 1996, Endocrinology.

[12]  E. Simpson,et al.  Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. , 1995, The Journal of clinical endocrinology and metabolism.

[13]  E. Albrecht,et al.  Actions of placental and fetal adrenal steroid hormones in primate pregnancy. , 1995, Endocrine reviews.

[14]  E. Simpson,et al.  A three‐dimensional model of aromatase cytochrome P450 , 1995, Protein science : a publication of the Protein Society.

[15]  Y. Ito,et al.  A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). , 1994, The Journal of clinical endocrinology and metabolism.

[16]  R T Turner,et al.  Skeletal effects of estrogen. , 1994, Endocrine reviews.

[17]  N. Harada,et al.  Biochemical and molecular genetic analyses on placental aromatase (P-450AROM) deficiency. , 1992, The Journal of biological chemistry.

[18]  J. Mathis,et al.  Structural analysis of the gene encoding human aromatase cytochrome P-450, the enzyme responsible for estrogen biosynthesis. , 1989, The Journal of biological chemistry.