title: Chronic administration of the metastin/kisspeptin analog KISS1-305 or the investigational agent TAK-448 suppresses hypothalamic pituitary gonadal function and depletes plasma testosterone in adult male rats.
abstract: Metastin/kisspeptin, a hypothalamic peptide, plays a pivotal role in controlling GnRH neurons. Here we studied the effect of chronic sc administration of two kisspeptin analogs, KISS1-305 and TAK-448, on hypothalamic-pituitary-gonadal function in male rats in comparison with a GnRH analogue leuprolide or bilateral orchiectomy (ORX). The prototype polypeptide, KISS1-305 (1-4 nmol/h), caused substantial elevations of plasma LH and testosterone, followed by abrupt reductions of both hormone levels. Notably, testosterone levels were reduced to castrate levels within 3 d and remained depleted throughout the 4-wk dosing period, an effect that was faster and more pronounced than leuprolide (1 nmol/h) dosing. KISS1-305 also reduced genital organ weight more profoundly than leuprolide. In mechanistic studies, chronic KISS1-305 administration only transiently induced c-Fos expression in GnRH neurons, suggesting that GnRH-neural response was attenuated over time. Hypothalamic GnRH content was reduced to 10-20% of control at 3 wk without any changes in Gnrh mRNA expression. Dosing with the investigational peptide TAK-448 was also studied to extend our understanding of hypothalamic-pituitary functions. Similar to ORX, TAK-448 (0.1 nmol/h) depleted testosterone and decreased GnRH content by 4 wk. However, in contrast to ORX, TAK-448 decreased gonadotropin levels in pituitary and plasma samples, implying the suppression of GnRH pulses. These results suggest that chronic administration of kisspeptin analogs disrupts endogenous kisspeptin signals to suppress intrinsic GnRH pulses, perhaps by attenuating GnRH-neural response and inducing continuous GnRH leakage from the hypothalamus. The potential utility of kisspeptin analogs as novel agents to treat hormone-related diseases, including prostate cancer, is discussed.
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company, Ltd., Kanagawa, Japan. hisanori.matsui@takeda.com
authors.forename: Hisanori
authors.initials: H
authors.lastname: Matsui
authors.forename: Akira
authors.initials: A
authors.lastname: Tanaka
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takatsu
authors.forename: Kaori
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Taiji
authors.initials: T
authors.lastname: Asami
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishizawa
authors.forename: Atsuko
authors.initials: A
authors.lastname: Suzuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kumano
authors.forename: Michiko
authors.initials: M
authors.lastname: Terada
authors.forename: Masami
authors.initials: M
authors.lastname: Kusaka
authors.forename: Chieko
authors.initials: C
authors.lastname: Kitada
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohtaki
mesh_terms: D000818:Animals; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D059648:Kisspeptins / Q000494:pharmacology*; D016729:Leuprolide / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009919:Orchiectomy; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000097:blood*
chemical_list: D059648:Kisspeptins; C577479:metastin (46-54), acetyl-tyrosyl(46)-hydroxypropyl(47)-threonyl(49)-azaglycyl(51)-methylarginyl(53)-tryptophyl(54)-; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D016729:Leuprolide