title: Elevated hypothalamic aromatization at the onset of precocious puberty in transgenic female mice hypersecreting human chorionic gonadotropin: effect of androgens.
abstract: Transgenic female mice overexpressing the α- and β- subunits of human chorionic gonadotropin (hCGαβ+) exhibited precocious puberty, as evidenced by early vaginal opening. Chronically elevated hCG in 21-day-old hCGαβ+ females stimulated gonadal androgen production, which exerted negative feedback over the endogenous gonadotropin synthesis, and activated the hypothalamic GnRH pulsatility and gene expression. Transgenic females also exhibited elevated hypothalamic aromatization in the preoptic area (POA), which is the sexually-differentiated area that controls the LH surge in adulthood. Ovariectomy at 14 days of age was unable to rescue this phenotype. However, the blockade of androgen action by flutamide from postnatal day 6 onwards reduced the aromatase levels in the POA of hCGαβ+ females. Our results suggest that early exposure of females to androgen action during a critical period between postnatal days 6-14 induces sex-specific organizational changes of the brain, which affect the aromatase expression in the POA at the onset of precocious puberty.
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina.
authors.forename: Betina
authors.initials: B
authors.lastname: Gonzalez
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Ratner
authors.affiliation: Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Casilla de Correo 389, 5000 Córdoba, Argentina.
authors.forename: María J
authors.initials: MJ
authors.lastname: Scerbo
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina.
authors.forename: Noelia P
authors.initials: NP
authors.lastname: Di Giorgio
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland; Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.affiliation: Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland; Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Ilpo T
authors.initials: IT
authors.lastname: Huhtaniemi
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina.
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Calandra
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina.
authors.forename: Victoria A R
authors.initials: VA
authors.lastname: Lux-Lantos
authors.affiliation: Instituto de Investigación Médica Mercedes y Martín Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Casilla de Correo 389, 5000 Córdoba, Argentina.
authors.forename: María J
authors.initials: MJ
authors.lastname: Cambiasso
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina. Electronic address: rulli.susana@gmail.com.
authors.forename: Susana B
authors.initials: SB
authors.lastname: Rulli
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000378:metabolism* / Q000502:physiology; D004958:Estradiol / Q000097:blood; D005260:Female; D005485:Flutamide / Q000494:pharmacology / Q000627:therapeutic use; D005640:Follicle Stimulating Hormone / Q000097:blood; D015870:Gene Expression; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism; D011629:Puberty, Precocious / Q000188:drug therapy / Q000378:metabolism*; D013739:Testosterone / Q000097:blood; D014621:Vagina / Q000503:physiopathology
chemical_list: D000726:Androgen Antagonists; D006063:Chorionic Gonadotropin; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; D005640:Follicle Stimulating Hormone; D001141:Aromatase
keywords: Aromatase; Human chorionic gonadotropin; Hypothalamic–pituitary–gonadal axis; Precocious puberty; Transgenic mice