title: Delayed puberty in spontaneously hypertensive rats involves a primary ovarian failure independent of the hypothalamic KiSS-1/GPR54/GnRH system.
abstract: Spontaneously hypertensive (SH) rats, extensively used as experimental models of essential human hypertension, display important alterations in the neuroendocrine reproductive axis, which manifest as markedly delayed puberty onset in females but whose basis remains largely unknown. We analyze herein in female SH rats: 1) possible alterations in the expression and function of KiSS-1/GPR54 and GnRH/GnRH-receptor systems, 2) the integrity of feedback mechanisms governing the hypothalamic-pituitary-ovarian axis, and 3) the control of ovarian function by gonadotropins. Our data demonstrate that, despite overtly delayed puberty, no significant decrease in hypothalamic KiSS-1, GPR54, or GnRH mRNA levels was detected in this strain. Likewise, in vivo gonadotropin responses to ovariectomy and systemic kisspeptin-10 or GnRH administration, as well as in vitro gonadotropin responses to GnRH, were fully preserved in SH rats. Moreover, circulating LH levels were grossly conserved during prepubertal maturation, whereas FSH levels were even enhanced from d 20 postpartum onwards. In striking contrast, ovarian weight and hormone (progesterone and testosterone) responses to human chorionic gonadotropin (CG) in vitro were profoundly decreased in SH rats, with impaired follicular development and delayed ovulation at puberty. Such reduced hormonal responses to human CG could not be attributed to changes in LH/CG or FSH-receptor mRNA expression but might be linked to blunted P450scc, 3beta-hydroxy steroid dehydrogenase, and aromatase mRNA levels in ovaries from SH rats. In conclusion, our results indicate that the expression and function of KiSS-1/GPR54 and GnRH/GnRH-receptor systems is normal in SH rats, whereas ovarian development, steroidogenesis, and responsiveness to gonadotropins are strongly compromised.
authors.affiliation: Medical Research Council Human Reproductive Sciences Unit, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: L
authors.initials: L
authors.lastname: Pinilla
authors.forename: J M
authors.initials: JM
authors.lastname: Castellano
authors.forename: M
authors.initials: M
authors.lastname: Romero
authors.forename: M
authors.initials: M
authors.lastname: Tena-Sempere
authors.forename: F
authors.initials: F
authors.lastname: Gaytán
authors.forename: E
authors.initials: E
authors.lastname: Aguilar
mesh_terms: D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007031:Hypothalamus / Q000378:metabolism*; D059648:Kisspeptins; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D010052:Ovariectomy; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016649:Primary Ovarian Insufficiency / Q000378:metabolism / Q000503:physiopathology*; D011506:Proteins / Q000378:metabolism*; D011628:Puberty, Delayed / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000074502:Receptors, Kisspeptin-1; D015398:Signal Transduction / Q000502:physiology
chemical_list: D006063:Chorionic Gonadotropin; C491406:Kiss1 protein, rat; C492247:Kiss1r protein, rat; D059648:Kisspeptins; D011506:Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone