title: Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis.
abstract: Hypothalamic thyrotropin-releasing hormone (TRH) stimulates thyroid-stimulating hormone (TSH) secretion from the anterior pituitary. TSH then initiates thyroid hormone (TH) synthesis and release from the thyroid gland. Although opposing TRH and TH inputs regulate the hypothalamic-pituitary-thyroid axis, TH negative feedback is thought to be the primary regulator. This hypothesis, however, has yet to be proven in vivo. To elucidate the relative importance of TRH and TH in regulating the hypothalamic-pituitary-thyroid axis, we have generated mice that lack either TRH, the beta isoforms of TH receptors (TRbeta KO), or both (double KO). TRbeta knock-out (KO) mice have significantly higher TH and TSH levels compared with wild-type mice, in contrast to double KO mice, which have reduced TH and TSH levels. Unexpectedly, hypothyroid double KO mice also failed to mount a significant rise in serum TSH levels, and pituitary TSH immunostaining was markedly reduced compared with all other hypothyroid mouse genotypes. This impaired TSH response, however, was not due to a reduced number of pituitary thyrotrophs because thyrotroph cell number, as assessed by counting TSH immunopositive cells, was restored after chronic TRH treatment. Thus, TRH is absolutely required for both TSH and TH synthesis but is not necessary for thyrotroph cell development.
authors.affiliation: Department of Medicine and the Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Amisra A
authors.initials: AA
authors.lastname: Nikrodhanond
authors.forename: Tania M
authors.initials: TM
authors.lastname: Ortiga-Carvalho
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shibusawa
authors.forename: Koshi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Xiao Hui
authors.initials: XH
authors.lastname: Liao
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamada
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D005260:Female; D005838:Genotype; D006579:Heterozygote; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000378:metabolism*; D020033:Protein Isoforms; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D013963:Thyroid Hormones; D013973:Thyrotropin-Releasing Hormone; D012313:RNA; D013972:Thyrotropin