Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice

Betina Gonzalez; Laura D Ratner; Noelia P Di Giorgio; Matti Poutanen; Ilpo T Huhtaniemi; Ricardo S Calandra; Victoria A R Lux-Lantos; Susana B Rulli

doi:10.1016/j.mce.2010.09.016

Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice

Mol Cell Endocrinol. 2011 Jan 30;332(1-2):78-87. doi: 10.1016/j.mce.2010.09.016. Epub 2010 Oct 7.

Authors

Betina Gonzalez¹, Laura D Ratner, Noelia P Di Giorgio, Matti Poutanen, Ilpo T Huhtaniemi, Ricardo S Calandra, Victoria A R Lux-Lantos, Susana B Rulli

Affiliation

¹ Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490 (1428), Buenos Aires, Argentina.

PMID: 20933053
DOI: 10.1016/j.mce.2010.09.016

Abstract

Transgenic male mice that express human chorionic gonadotropin (hCG) α and β subunits constitutively hypersecrete hCG and produce elevated levels of androgens. The aim of this study was to characterize the hypothalamic-pituitary function of these transgenic (hCGαβ+) males by focusing on FSH regulation. Serum FSH levels and pituitary mRNA expression of Fshb, Lhb, Cga, Gnrhr and Esr1 were reduced, whereas Fst expression was increased in prepubertal hCGαβ+ males as compared with wild-type. In the hypothalamus, Cyp19a1 expression, GnRH concentration and ex-vivo GnRH pulsatility were elevated in prepubertal hCGαβ+ mice, whereas Kiss1 expression was decreased prepubertally and Gad67 expression was elevated neonatally. The effect of androgens on the developmental programming of the hypothalamic-pituitary axis of hCGαβ+ males was evaluated by perinatal and prepubertal antiandrogen (flutamide) administration. Our studies identified a critical window between gestational day 18 and postnatal day 14, during which chronically elevated androgens and/or their locally produced metabolites activate the hypothalamus and concomitantly shut-down the gonadotropin axis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen Antagonists / metabolism
Androgens / metabolism*
Animals
Aromatase / genetics
Aromatase / metabolism
Castration
Chorionic Gonadotropin, beta Subunit, Human / genetics
Chorionic Gonadotropin, beta Subunit, Human / metabolism*
Follicle Stimulating Hormone / blood
Follicle Stimulating Hormone / genetics
Gene Expression
Glutamate Decarboxylase / genetics
Glutamate Decarboxylase / metabolism
Glycoprotein Hormones, alpha Subunit / genetics
Glycoprotein Hormones, alpha Subunit / metabolism*
Gonadotropin-Releasing Hormone / genetics
Gonadotropin-Releasing Hormone / metabolism
Humans
Hypothalamo-Hypophyseal System / growth & development*
Hypothalamo-Hypophyseal System / metabolism*
Hypothalamus / physiology
Kisspeptins
Luteinizing Hormone / blood
Luteinizing Hormone / genetics
Male
Mice
Mice, Transgenic
Pituitary Gland / physiology
Proteins / genetics
Proteins / metabolism
Puberty / physiology

Substances

Androgen Antagonists
Androgens
Chorionic Gonadotropin, beta Subunit, Human
Glycoprotein Hormones, alpha Subunit
Kiss1 protein, mouse
Kisspeptins
Proteins
Gonadotropin-Releasing Hormone
Luteinizing Hormone
Follicle Stimulating Hormone
Aromatase
Glutamate Decarboxylase
glutamate decarboxylase 1